MAP4K1 inhibitors

ABSTRACT

One embodiment of the disclosure is a compound represented by Formula I or a pharmaceutically acceptable salt thereof. The variables in Formula I are defined herein. Compounds of Formula I are selective MAP4K1 inhibitors, which can be used to treat a diseases or disorders in a subject that benefits from control of MAP4K1 activity.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalApplication No. 62/961,463, filed on Jan. 15, 2020, the entire contentsof which is incorporated herein by reference.

SEQUENCE LISTING

This application contains a Sequence Listing which has been submittedelectronically in ASCII format and is hereby incorporated by referencein its entirely. Said ASCII copy, created on Jan. 14, 2021, is named131608-80102_SL.TXT and is 1,052 bytes in size.

FIELD

This application is directed to MAP4K1 inhibitors and methods for theiruse, such as to control the activity of MAP4K1 in a subject.

BACKGROUND

MAP4K1, also known as hematopoietic progenitor kinase 1 (HPK1), wasoriginally cloned from hematopoietic progenitor cells (Hu, M. C., etal., Genes Dev, 1996. 10(18): p. 2251-64). MAP4K1 is of particularinterest as a target, because it is predominantly expressed inhematopoietic cells such as T cells, B cells, macrophages, dendriticcells, neutrophils, and mast cells (Hu, M. C., et al, Genes Dev, 1996.10(18): p. 2251-64; Kiefer, F., et al, EMBO J, 1996. 15(24): p.7013-25). MAP4K1 kinase activity has been shown to be induced uponactivation of T cell receptors (TCR) (Liou, J., et al., Immunity, 2000.12(4): p. 399-408), B cell receptors (BCR) (Liou, J., et al., Immunity,2000. 12(4): p. 399-408), transforming growth factor receptor (TGF-R)(Wang, W., et al, J Biol Chem, 1997. 272(36): p. 22771-5; Zhou, G., etal, J Biol Chem, 1999. 274(19): p. 13133-8), or G_(s)-coupled PGE₂receptors (EP2 and EP4) (Ikegami, R, et al, J Immunol, 2001. 166(7): p.4689-96). As such, MAP4K1 regulates diverse functions of various immunecells.

MAP4K1 is important in regulating the functions of various immune cellsand it has been implicated in autoimmune diseases and anti-tumorimmunity (Shui, J. W., et al, Nat Immunol, 2007. 8(1): p. 84-91; Wang,X., et al, J Biol Chem, 2012. 287(14): p. 11037-48). Those observationssuggested that attenuation of MAP4K1 activity may contribute toautoimmunity in patients. Furthermore, MAP4K1 may also controlanti-tumor immunity via T cell-dependent mechanisms. In thePGE2-producing Lewis lung carcinoma tumor model, the tumors developedmore slowly in MAP4K1 knockout mice as compared to wild-type mice (seeUS 2007/0087988). In addition, it was shown that adoptive transfer ofMAP4K1 deficient T cells was more effective in controlling tumor growthand metastasis than wild-type T cells (Alzabin, S., et al., CancerImmunol Immunother, 2010. 59(3): p. 419-29). Similarly, bone marrowderived dendritic cells (BMDCs) from MAP4K1 knockout mice were moreefficient to mount a T cell response to eradicate Lewis lung carcinomaas compared to wild-type BMDCs (Alzabin, S., et al., J Immunol, 2009.182(10): p. 6187-94). Data obtained from MAP4K1 kinase dead micedemonstrated that MAP4K1 kinase activity is critical in conferringsuppressive functions of MAP4K1 in a wide range of immune cellsincluding CD4+, CD8+, DC, NK to T regulatory cells (Tregs) andinactivation of kinase domain was sufficient to elict robust anti-tumorimmune responses. Liu et at, PLoS ONE 14(3):e0212670https://doi.org/10.1371/journal.pone.0212670. Moreover, loss of MAP4K1kinase function suppresses tumor growth in preclinical tumor models andtherapeutic co-blockade of MAP4K1 kinase and PD-L1 enhances anti-tumorresponses. Hernandez S. et al., Cell Reports 2018 25: p. 80-94. Recentlypresented results show tumor growth inhibition in a CT-26 syngeneicmouse model using a small molecule (Seungmook, L., Cancer research.AACRJournal, 2019, Abstract 4150). These data have validated MAP4K1 as anovel drug target for enhancing antitumor immunity. Accordingly, thereis a need for new compounds that modulate MAP4K1 activity for thetreatment of MAP4K1-dependent diseases or disorders such as cancer,viral infection, and other diseases and disorders.

SUMMARY

Provided herein are compounds and compositions which inhibit MAP4K1,thereby enhancing an immune response in a subject. For example, the IC₅₀values for inhibition of MAP4K1 provided in Example 19 demonstrate thatthese compounds are potent inhibitors of MAP4K1. Compounds provided herein are selective inhibitors of MAP4K1. Also disclosed are methods ofusing the compounds and compositions described herein for treatingcancer and viral infection

One embodiment of the disclosure is a compound represented by Formula I:

or a pharmaceutically acceptable salt thereof,wherein:

A¹ and A² are selected from N and CH;

A³ is selected from CH and N;

X is selected from C₁₋₃ alkyl, OR⁶, NHR⁷ and halogen;

B is selected from CR¹¹ and N, Y is selected from N and CR¹², and thebond between Y and B is a double bond; or

B is C(O), Y is NR¹⁴, and the bond between Y and B is a single bond; orY and B taken together form a 5 to 7-membered heterocycle or C₅₋₆cycloalkyl, and the bond between Y and B is a double bond, wherein saidheterocycle or cycloalkyl is optionally substituted with 1-6 R⁸;

each R⁸ is independently selected from C₁₋₃ alkyl and OH, or

two R⁸ attached to the same carbon form an oxo, or

two R⁸ attached to the same carbon atom taken together with the carbonatom to which they are attached a form a C₃₋₅ cycloalkyl, or

two R⁸ attached to two adjacent carbon atoms taken together with the twoadjacent carbon atoms to which they are attached form a C₃₋₆ cycloalkyl,wherein said alkyl and cycloalkyl are optionally substituted with 1-6halogen;

R¹ and R² are each independently selected from hydrogen, C₁₋₄ alkyl,C₃₋₅ cycloalkyl, and 3 to 5-membered heterocycle, wherein said alkyl andcycloalkyl are optionally substituted with OH, C₁₋₆alkoxy or 1-6halogen; or

R¹ and R², taken together with the atoms to which they are attached,form a 4 to 6-membered heterocycle or C₃₋₆ cycloalkyl;

R³ and R⁴ are each independently selected from hydrogen, C₁₋₆ alkyl,C₁₋₆ alkyl substituted with OR¹⁶, C₃₋₆ cycloalkyl and 4 to 6-memberedheterocycle; or

R³ and R⁴ taken together with the atoms to which they are attached, forma C₃₋₆ cycloalkyl or 4 to 6-membered heterocycle; or

R¹ and R³, taken together with the atoms to which they are attached,form a 3 to 6-membered heterocycle;

R⁶ is selected from C₁₋₃ alkyl, C₃₋₆ cycloalkyl and 4 to 6-memberedheterocycle, wherein said alkyl, cycloalkyl, and heterocycle areoptionally substituted with 1-3 R⁹;

R⁷ is selected from hydrogen, C₁₋₃ alkyl, C₃₋₅ cycloalkyl and 4 to6-membered heterocycle, wherein said alkyl, cycloalkyl, and heterocycleare optionally substituted with 1-3 R⁹;

R⁹ is selected from C₁₋₃ alkyl, C₃₋₆ cycloalkyl substituted withhalogen, halogen, SO₂Me, C₁₋₃ alkoxy and OH;

R¹¹ is selected from hydrogen, COON, CN, halogen, and C₁₋₃ alkoxy;

R¹² is selected from C₁₋₅ alkyl, C₄₋₆ cycloalkyl, 3 to 6-memberedheterocycle, NHR¹³, NR¹³R¹³ and OR¹³, wherein said alkyl, cycloalkyl orheterocycle is optionally substituted with OH, NH₂, 1-4 halogen or R¹⁵;

each R¹³ is independently selected from C₁₋₆ alkyl and C₃₋₆ cycloalkyl,wherein said alkyl or cycloalkyl is optionally substituted with halogen;

R¹⁴ is selected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl and 4 to 6-memberedheterocycle, wherein said alkyl, cycloalkyl or heterocycle is optionallysubstituted with 1-6 halogen;

R¹⁵ is OH, C₁₋₃ alkyl or C₃₋₅ cycloalkyl; and

R¹⁶ is H or C₁₋₃ alkyl.

Another embodiment of the disclosure is a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier or excipient and acompound disclosed herein or a pharmaceutically acceptable salt thereof.

Another embodiment of the disclosure is a method of treating aMAP4K1-dependent disorder or disease (e.g., treating a cancer or viralinfection), comprising administering to the subject an effective amountof a compound disclosed herein or a pharmaceutically acceptable saltthereof or a pharmaceutical composition comprising the compound(s).

Another embodiment of the disclosure is the use of a compound disclosedherein or a pharmaceutically acceptable salt thereof or a pharmaceuticalcomposition comprising the compound(s), for the preparation of amedicament for treating a MAP4K1-dependent disorder or disease (e.g.,treating a cancer or viral infection).

Another embodiment of the disclosure is a compound disclosed herein or apharmaceutically acceptable salt thereof or a pharmaceutical compositioncomprising the compound(s), for use in treating a MAP4K1-dependentdisorder or disease (e.g., treating a cancer or viral infection).

DETAILED DESCRIPTION

The disclosed compounds are MAP4K1 inhibitors, which can be used fortreating a MAP4K1-dependent disorder or disease. Such diseases ordisorders include cancer and viral infection.

Compound Embodiments

Example embodiments include:

First embodiment: a compound represented by Formula I, or apharmaceutically acceptable salt thereof. The variables in Formula I aredescribed above in the summary.

Second embodiment: a compound represented by Formula I, or apharmaceutically acceptable salt thereof, wherein:

X is selected from OR⁶, NHR⁷ and halogen;

R³ and R⁴ are each independently selected from hydrogen, C₁₋₆ alkylsubstituted with OH, C₁₋₆ alkyl, C₃₋₆ cycloalkyl and 4 to 6-memberedheterocycle; or

R³ and R⁴, taken together with the atoms to which they are attached,form a C₃₋₆ cycloalkyl or 4 to 6-membered heterocycle; or

R¹ and R³, taken together with the atoms to which they are attached,form a 3 to 6-membered heterocycle; and

the remainder of the variables in Formula I are described above in thefirst embodiment.

Third embodiment: a compound represented by Formula I, or apharmaceutically acceptable salt thereof, wherein:

R¹ and R² are each independently selected from hydrogen, C₁₋₄ alkyloptionally substituted with OH, cyclobutyl, and oxetanyl;

R³ and R⁴ are each independently selected from hydrogen, C₁₋₆ alkyl andC₃₋₆ cycloalkyl; or R¹ and R³, taken together with the atoms to whichthey are attached, form a 3 to 6-membered heterocycle;

each R⁸ is independently C₁₋₃ alkyl; or

two R⁸ attached to the same carbon form an oxo; or

two R⁸ attached to the same carbon atom taken together with the carbonatom to which they are attached form a C₃₋₅ cycloalkyl; or

two R⁸ attached to two adjacent carbon atoms taken together with the twoadjacent carbon atoms to which they are attached form C₃₋₆ cycloalkyl;

R⁶ is selected from C₁₋₃ alkyl and C₃₋₆ cycloalkyl, wherein said alkyland cycloalkyl are optionally substituted with 1 to 3 R⁹;

R⁷ is selected from C₁₋₃ alkyl and C₃₋₆ cycloalkyl;

R¹¹ is selected from COOH and CN;

R¹² is selected from C₁₋₅ alkyl, C₄₋₆ cycloalkyl, 3 to 6-memberedheterocycle and OR¹³, wherein said alkyl, cycloalkyl, or heterocycle isoptionally substituted with OH, NH₂, 1 to 4 halogen or R¹⁵;

R¹³ is C₁₋₆ alkyl;

R¹⁴ is C₁₋₆ alkyl; and

R¹⁵ is C₁₋₃ alkyl; and

the remainder of the variables in Formula I are described above in thefirst and/or second embodiments.

Fourth embodiment: a compound represented by Formula II:

or a pharmaceutically acceptable salt thereof. The variables in FormulaII are described above in the first, second and/or the thirdembodiments.

Fifth embodiment: a compound represented by Formula III:

or a pharmaceutically acceptable salt thereof. The variables in FormulaIII are described abovein the first, second and/or the third embodiments.

Sixth embodiment: a compound represented by Formula IV:

or a pharmaceutically acceptable salt thereof. The variables in FormulaIV are described above in the first, second and/or the thirdembodiments.

Seventh embodiment: a compound represented by Formula V or VI:

or a pharmaceutically acceptable salt thereof, wherein E is CH₂, NH, orO; each R⁸ is C₁₋₃ alkyl, and n is 0 to 4; two R⁸ attached to the samecarbon atom taken together with the carbon atom to which they areattached form a C₃₋₅ cycloalkyl; or two R⁸ attached to two adjacentcarbon atoms taken together with the two adjacent carbon atoms to whichthey are attached form a C₄₋₆ cycloalkyl. Alternatively, E is NH. Inanother alternative, E is O. The remainder of the variables in FormulasV and VI are described above in the first, second and/or the thirdembodiments.

Eighth embodiment: a compound represented by Formula V(A) or VI(A):

or a pharmaceutically acceptable salt thereof. The variables in FormulasV(A) and VI(A) are described above in the first, second, third and/orthe seventh embodiments.

Ninth embodiment: a compound represented by Formula V(B) or VI(B):

or a pharmaceutically acceptable salt thereof. The variables in FormulasV(B) and VI(B) are described above in the first, second, third and/orthe seventh embodiments.

Tenth embodiment: a compound represented by Formula V(C) or VI(C):

or a pharmaceutically acceptable salt thereof. The variables in FormulasV(C) and VI(C) are described above in the first, second, third and/orthe seventh embodiments.

Eleventh embodiment: a compound represented by any one of Formulas I, V,VI, V(A), VI(A), V(B), VI(B), V(C) and VI(C), or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is methyl and n is 0, 1, 2, 3 or 4.Alternatively, R⁸ is methyl and n is 1; R⁸ is methyl and n is 2; R⁸ ismethyl and n is 3; R⁸ is methyl and n is 4; R⁸ is ethyl and n is 0, 1,2, or 3; R⁸ is ethyl and n is 1; R⁸ is ethyl and n is 2; or R⁸ is ethyland n is 3 The remainder of the variables in Formulas I, V, VI, V(A),VI(A), V(B), VI(B), V(C) and VI(C) are as described above in the first,second, third and/or the seventh embodiments.

Twelfth embodiment: a compound represented by any one of Formulas I, V,VI, V(A), VI(A), V(B), VI(B), V(C) and VI(C), or a pharmaceuticallyacceptable salt thereof, wherein two R⁸ attached to the same carbon atomtaken together with the carbon atom to which they are attached form acyclopropyl; or two R⁸ attached to two adjacent carbon atoms takentogether with the two adjacent carbon atoms to which they are attachedform a cyclopentyl. Alternatively, two R⁸ attached to the same carbonatom taken together with the carbon atom to which they are attached forma cyclobutyl. In another alternative, two R⁸ attached to the same carbonatom taken together with the carbon atom to which they are attached forma cyclopentyl. In another alternative, two R⁸ attached to two adjacentcarbon atoms taken together with the two adjacent carbon atoms to whichthey are attached form a cyclobutyl. In yet another embodiment, two R⁸attached to two adjacent carbon atoms taken together with the twoadjacent carbon atoms to which they are attached form a cyclopropyl. Theremainder of the variables in Formulas I, V, VI, V(A), VI(A), V(B),VI(B), V(C) and VI(C) are as described above in the first, second, thirdand/or the seventh embodiments.

Thirteenth embodiment: a compound represented by Formula VII, VIII orIX:

or a pharmaceutically acceptable salt thereof. The variables in FormulasVII, VIII and IX are as described above in the first, second and/or thethird embodiments.

Fourteenth embodiment: a compound represented by Formula VII(A), VIII(A)or IX(A):

or a pharmaceutically acceptable salt thereof. The variables in FormulasVII(A), VIII(A) and IX(A) are as described above in the first, secondand/or the third embodiments.

Fifteenth embodiment: a compound represented by any one of FormulasI-IV, VII-IX and VII(A)-IX(A), or a pharmaceutically acceptable saltthereof, wherein R¹¹ is CN. The remainder of the variables in FormulasI-IV, VII-IX and VII(A)-IX(A) are as described above in the first,second and/or the third embodiments.

Sixteenth embodiment: a compound represented by any one of FormulasI-IV, VII-IX and VII(A)-IX(A), or a pharmaceutically acceptable saltthereof, wherein R¹² is selected from isopropyl, fluoropropyl,trifluoroisopropyl, isobutyl, tert-butyl, isopropyloxy,methylpyrrolidine, methylazetidine, and hydroxycyclohexyl. The remainderof the variables in Formulas I-IV, VII-IX and VII(A)-IX(A) are asdescribed above in the first, second, third and/or the fifteenthembodiments.

Seventeenth embodiment: a compound represented by Formula X:

or a pharmaceutically acceptable salt thereof. The variables in FormulaX are as described above in the first, second and/or the thirdembodiments.

Eighteenth embodiment: a compound represented by any one of FormulasI-IV and X, or a pharmaceutically acceptable salt thereof, wherein R¹⁴is isobutyl. The remainder of the variables in Formulas I-IV and X areas described above in the first, second and/or the third embodiments.

Nineteenth embodiment: a compound represented by any one of FormulasI-IV, V(A)-V(C), VI(A)-VI(C), VII-IX, VII(A)-IX(A) and X, or apharmaceutically acceptable salt thereof, wherein X is OR⁶, and R⁶ isselected from methyl, ethyl, propyl, isopropyl, trifluoroethyl,trifluoroisopropyl, difluoroethyl, difluoropropyl, difluoroisopropyl,oxetanyl, tetrahydrofuranyl, cyclobutyl, and cyclopropyl, whereincyclopropyl is optionally substituted with methyl or one or two fluoro,wherein cyclobutyl is optionally substituted with OH, wherein oxetanylis optionally substituted with methyl. The remainder of the variables inFormulas I-IV and X are as described above in the first, second, third,seventh, eleventh, twelfth, fifteenth, sixteenth and/or the eighteenthembodiments.

Twentieth embodiment: a compound represented by any one of FormulasI-IV, V(A)-V(C), VI(A)-VI(C), VII-IX, VII(A)-IX(A) and X, or apharmaceutically acceptable salt thereof, wherein X is OR⁶, and R⁶ isselected from methyl, ethyl, propyl, isopropyl, trifluoroethyl,trifluoroisopropyl, difluoroethyl, difluoropropyl, difluoroisopropyl,oxetanyl, tetrahydrofuranyl, cyclobutyl, and cyclopropyl, whereincyclopropyl is optionally substituted with methyl or one or two fluoro.Alternatively, R⁶ is methyl; in another alternative, R⁶ is ethyl; inanother alternative, R⁶ is trifluoroethyl; in another alternative, R⁶ isdifluoroethyl; in another alternative, R⁶ is propyl; in anotheralternative, R⁶ is difluoropropyl; in another alternative, R⁶ isisopropyl; in another alternative, R⁶ is trifluoroisopropyl; in anotheralternative, R⁶ is difluoroisopropyl; in another alternative, R⁶ ismethylsulfonylethyl; in another alternative, R⁶ is cyclopropyl; inanother alternative, R⁶ is cyclobutyl; in another alternative, R⁶ isoptionally substituted with R⁹, wherein R⁹ is C₁₋₃ alkyl, C₃₋₆cycloalkyl substituted with halogen, halogen, C₁₋₃alkoxy, and OH; inanother alternative, R⁶ is cyclopropyl substituted with R⁹, wherein R⁹is methyl or one or two fluoro; in another alternative R⁶ is oxetanyl;in another alternative R⁶ is tetrahydropyranyl; in another alternativeR⁶ is tetrahydrofuranyl; and in yet another alternative R⁶ iscyclopropyl substituted with methyl. The remainder of the variables inFormulas I-IV, V(A)-V(C), VI(A)-VI(C), VII-IX, VII(A)-IX(A) and X are asdescribed above in the first, second, third, seventh, eleventh, twelfth,fifteenth, sixteenth and/or eighteenth embodiments.

Twenty-first embodiment: a compound represented by any one of FormulasI-IV, V(A)-V(C), VI(A)-VI(C), VII-IX, VII(A)-IX(A) and X, or apharmaceutically acceptable salt thereof, wherein X is NHR⁷, and R⁷ isselected from methyl, ethyl, cyclopropyl and cyclobutyl. The remainderof the variables in Formulas I-IV, V(A)-V(C), VI(A)-VI(C), VII-IX,VII(A)-IX(A) and X are described above in the first, second, third,seventh, eleventh, twelfth, fifteenth, sixteenth and/or eighteenthembodiments.

Twenty-second embodiment: a compound represented by any one of FormulasI-IV, V(A)-V(C), VI(A)-VI(C), VII-IX, VII(A)-IX(A) and X, or apharmaceutically acceptable salt thereof, wherein X is methyl. Theremainder of the variables in Formulas I-IV, V(A)-V(C), VI(A)-VI(C),VII-IX, VII(A)-IX(A) and X are described above in the first, second,third, seventh, eleventh, twelfth, fifteenth, sixteenth and/oreighteenth embodiments.

Twenty-third embodiment: a compound represented by any one of FormulasI-IV, V(A)-V(C), VI(A)-VI(C), VII-IX, VII(A)-IX(A) and X, or apharmaceutically acceptable salt thereof, wherein R³ and R⁴ are eachindependently selected from hydrogen, methyl, methyl substituted withOCH₃, ethyl, hydroxymethyl, cyclopropyl and cyclobutyl. The remainder ofthe variables in Formulas I-IV, V(A)-V(C), VI(A)-VI(C), VII-IX,VII(A)-IX(A) and X are described above in the first, second, third,seventh, eleventh, twelfth, fifteenth, sixteenth, eighteenth,nineteenth, twentieth, twentyfirst and/or twentysecond embodiments.

Twenty-fourth embodiment: a compound represented by any one of FormulasI-IV, V(A)-V(C), VI(A)-VI(C), VII-IX, VII(A)-IX(A) and X, or apharmaceutically acceptable salt thereof, wherein R³ and R⁴ are eachindependently selected from hydrogen, methyl, hydroxymethyl, ethyl,cyclopropyl and cyclobutyl. Alternatively, R³ and R⁴ are eachindependently selected from C₁₋₆ alkyl and C₃₋₆cycloalkyl; in anotheralternative, R³ and R⁴ are each independently selected from C₁₋₃ alkyland cyclopropyl; in another alternative, R³ is methyl and R⁴ is methyl;in another alternative, R³ is H and R⁴ is methyl; in another alternativeR³ is ethyl and R⁴ is methyl; in another alternative R³ is CH₂OH and R⁴is methyl; in another alternative, R³ is methyl and R⁴ is cyclopropyl;in another alternative, and in yet another alternative R³ is methyl andR⁴ is cyclobutyl. The remainder of the variables in Formulas I-IV,V(A)-V(C), VI(A)-VI(C), VII-IX, VII(A)-IX(A) and X are described abovein the first, second, third, seventh, eleventh, twelfth, fifteenth,sixteenth, eighteenth, nineteenth, twentieth and/or twentyfirstembodiments.

The disclosure also includes the compounds depicted in Table 1 andprepared in the Exemplification. The synthetic protocol used to preparecompounds in Table 1 is listed in the last column of Table 1 and fulldetails for each synthetic protocol are described in Schemes 1-17 in theGeneral Synthetic Methods and Intermediates section.

TABLE 1 LCMS Synthetic # Structure (M + 1) NMR Protocol 1

357 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.23 (br s, 1H), 8.74 (br s, 1H),8.30 (br s, 1H), 8.09 (br d, J = 3.2 Hz, 1H), 7.08 (br s, 1H), 4.60 (brs, 1H), 4.02 (br d, J = 4.0 Hz, 3H), 1.84-1.61 (m, 6H), 1.49 (br s, 3H),1.19 (br s, 1H) 1 Second eluting isomer 2

366 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.56 (s, 1H), 8.53 (d, J = 7.2 Hz,1H), 8.39 (d, J = 6.8 Hz, 1H), 8.05 (s, 1H), 7.61 (s, 1H), 3.25 (s, 3H),1.97 (s, 6H), 1.50 (s, 9H) 3 3

367 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.39 (s, 1H), 8.58 (s, 1H), 8.34 (d,J = 5.6 Hz, 1H), 8.19 (s, 1H), 7.47 (d, J = 6.0 Hz, 1H), 4.12 (s, 3H),1.76 (s, 6H), 1.45 (s, 9H). 2 4

369 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.51 (s, 1H), 8.39 (s, 1H), 8.25 (d,J = 6.8 Hz, 1H), 8.05 (s, 1H), 7.74-7.67 (m, 1H), 5.41-5.48 (m, 1H),4.18 (s, 3H), 2.00 (s, 6H), 1.46 (d, J = 6.4 Hz, 6H) 3 5

370 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.42 (s, 1H), 9.03 (s, 1H), 8.35 (d,1H, J = 6.0 Hz), 7.76 (d, 1H, J = 8.4 Hz), 7.28 (d, 1H, J = 5.6 Hz),6.85 (d, 1H, J = 8.4 Hz), 4.05 (s, 3H), 1.80 (t, 13H, J = 10.8 Hz). 4 6

370 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.22 (s, 1H), 8.89 (s, 1H), 8.37 (d,J = 6.0 Hz, 1H), 8.04 (s, 1H), 7.32 (d, J = 6.0 Hz, 1H), 3.05 (s, 3H),1.81 (s, 3H), 1.76 (s, 3H), 1.74 (s, 6H) 5 7

371 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.38 (s, 1H), 9.12 (s, 1H), 8.40 (d,J = 6.0 Hz, 1H), 8.14 (s, 1H), 7.25 (d, J = 6.0 Hz, 1H), 4.13 (s, 3H),1.83 (s, 6H), 1.82 (s, 3H), 1.77 (s, 3H) 3 8

377 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.49 (s, 1H), 9.08 (s, 1H), 8.28 (s,1H), 7.56 (s, 1H), 3.55- 3.46 (m, 1H), 3.24 (s, 3H), 2.00 (s, 6H), 1.42(d, J = 7.2 Hz, 6H) 6 9

378 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.52 (s, 1H), 9.32 (d, J = 0.8 Hz,1H), 8.20 (s, 1H), 8.12 (d, J = 8.8 Hz, 1H), 7.07 (d, J = 8.8 Hz, 1H),4.13 (s, 3H), 3.16 (t, J = 6.0 Hz, 2H), 2.73-2.62 (m, 2H), 2.22 (m, 2H),1.84 (s, 6H) 3 10

378 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.49 (s, 1H), 8.81 (s, 1H), 8.49 (s,1H), 8.00 (s, 1H), 4.72- 4.63 (m, 1H), 4.18 (s, 3H), 3.57-3.45 (m, 1H),2.03 (s, 6H), 1.44 (d, J = 7.2 Hz, 6H) 3 11

379 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.44 (s, 1H), 9.34 (s, 1H), 8.18 (s,1H), 8.12 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H), 4.14 (s, 3H),3.64 (t, J = 6.8 Hz, 2H), 3.17 (t, J = 6.8 Hz, 2H), 1.83 (s, 6H) 3 12

380 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 10.71 (s, 1H), 9.61 (s, 1H), 9.30(s, 1H), 8.20 (s, 1H), 9.09 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 8.8 Hz,1H), 4.59 (t, J = 6.0 Hz, 2H), 4.06 (s, 3H), 3.16 (t, J = 5.6 Hz, 2H),1.91 (s, 2H), 1.69 (s, 6H) 3 13

380 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.34 (s, 1H), 8.59 (s, 1H), 8.17 (s,1H), 7.98 (d, J = 5.6 Hz, 1H), 6.74 (d, J = 5.6 Hz, 1H), 4.60-4.51 (m,1H), 4.23-4.15 (m, 1H), 4.11 (s, 3H), 4.08-4.00 (m, 1H), 2.58-2.47 (m,1H), 2.05-1.95 (m, 1H), 1.73 (d, J = 1.6 Hz, 6H), 1.51 (d, J = 6.4 Hz,3H) 3 14

383 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.36 (s, 1H), 8.34 (s, 1H), 8.11 (s,1H), 7.65 (d, J = 9.6 Hz, 1H), 7.01 (d, J = 9.6 Hz, 1H), 5.18-5.09 (m,1H), 4.13 (s, 1H), 2.16-2.04 (m, 1H), 1.85 (d, J = 3.6 Hz, 6H),1.83-1.79 (m, 1H), 1.47 (d, J = 6.4 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H) 3Intermediate 3 15

383 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.36 (s, 1H), 8.34 (s, 1H), 8.11 (s,1H), 7.65 (d, J = 9.6 Hz, 1H), 7.01 (d, J = 9.6 Hz, 1H), 5.18-5.09 (m,1H), 4.13 (s, 1H), 2.16-2.04 (m, 1H), 1.85 (d, J = 3.6 Hz, 6H),1.83-1.79 (m, 1H), 1.47 (d, J = 6.4 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H) 3Intermediate 4 16

385 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.39 (s, 1H), 9.08 (s, 1H), 8.39 (d,J = 6.0 Hz, 1H), 8.17 (s, 1H), 7.28 (d, J = 5.6 Hz, 1H), 4.60-4.53 (m,2H), 1.82 (s, 3H), 1.77 (s, 9H), 1.51 (t, J = 6.8 Hz, 3H) 3 17

385 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.37 (s, 1 H), 9.31 (s, 1 H), 8.39(d, J = 6.0 Hz, 1 H), 8.03 (s, 1 H), 7.29 (d, J = 6.0 Hz, 1 H), 4.13 (s,3 H), 2.07 (s, 3 H), 1.83 (s, 3 H) 1.78 (s, 3 H), 1.69 (s, 6 H) 10 18

391 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.43 (s, 1H), 8.42 (s, 1H), 7.96 (s,1H), 7.89 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 4.16 (s, 3H),3.30- 3.22 (m, 1H), 2.02 (d, J = 3.2 Hz, 6H), 2.00-1.93 (m, 1H),1.84-1.73 (m, 1H), 1.41 (d, J = 6.8 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H) 3Intermediate 7 19

391 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.37 (s, 1H), 8.70 (s, 1H), 8.17 (s,1H), 7.86 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 4.12 (s, 3H),3.29- 3.20 (m, 1H), 2.08-1.96 (m, 1H), 1.83-1.75 (m, 7H), 1.41 (d, J =6.8 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H) 3 Intermediate 8 20

392 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.49 (s, 1H), 8.76 (s, 1H), 8.54 (s,1H), 7.99 (s, 1H), 4.18 (s, 3H), 3.28-3.23 (m, 1H), 2.02 (d, J = 3.2 Hz,6H), 2.00-1.92 (m, 1H), 1.87- 1.78 (m, 1H), 1.42 (d, J = 6.8 Hz, 3H),0.94 (t, J = 7.6 Hz, 3H). 3 Intermediate 29 21

392 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.49 (s, 1H), 8.76 (s, 1H), 8.54 (s,1H), 7.99 (s, 1H), 4.18 (s, 3H), 3.28-3.23 (m, 1H), 2.02 (d, J = 3.2 Hz,6H), 2.00-1.92 (m, 1H), 1.87- 1.78 (m, 1H), 1.42 (d, J = 6.8 Hz, 3H),0.94 (t, J = 7.6 Hz, 3H). 3 Intermediate 30 22

394 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.36 (s, 1H), 9.23 (s, 1H), 8.15 (d,J = 8.8 Hz, 1H), 8.10 (s, 1H), 7.25 (d, J = 8.4 Hz, 1H), 4.71-4.67 (m,1H), 4.44-4.41 (m, 1H), 4.14 (s, 3H), 3.20-3.14 (m, 1H), 1.93 (s, 3H),1.91 (s, 3H), 1.49 (d, J = 7.2 Hz, 3H) 3, first eluting isomer 23

394 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.35 (s, 1H), 9.25 (s, 1H), 8.14 (d,J = 9.2 Hz, 1H), 8.13 (s, 1H), 7.24 (d, J = 8.4 Hz, 1H), 4.71-4.67 (m,1H), 4.44-4.40 (m, 1H), 4.13 (s, 3H), 3.20-3.14 (m, 1H), 1.90 (s, 3H),1.88 (s, 3H), 1.48 (d, J = 7.2 Hz, 3H) 3, second eluting isomer 24

394 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 10.69 (s, 1H), 9.56 (s, 1H), 9.29(d, J = 0.8 Hz, 1H), 8.18 (s, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.31 (d, J= 8.8 Hz, 1H), 4.87-4.77 (m, 1H), 4.05 (s, 3H), 3.10- 3.01 (m, 2H), 1.68(d, J = 2.0 Hz, 6H), 1.46 (d, J = 6.4 Hz, 3H) 3, first eluting isomer 25

394 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 10.70 (s, 1H), 9.57 (s, 1H), 9.29(s, 1H), 8.19 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 8.8 Hz,1H), 4.89- 4.77 (m, 1H), 4.06 (s, 3H), 3.11-3.03 (m, 2H), 1.68 (d, J =2.0 Hz, 6H), 1.47 (d, J = 6.4 Hz, 3H) 3, second eluting isomer 26

394 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.40 (s, 2H), 8.25 (s, 1H), 8.01 (d,J = 8.4 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 4.15 (s, 3H), 1.86 (s, 6H),1.78 (s, 6H) 3 27

394 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.32 (s, 1H), 8.54 (s, 1H), 8.16 (s,1H), 7.97 (d, J = 6.0 Hz, 1H), 6.71 (s, 1H), 4.43- 4.33 (m, 1H), 4.10(s, 3H), 3.79-3.69 (m, 1H), 3.65-3.56 (m, 1H), 2.20- 2.08 (m, 2H),2.06-1.96 (m, 1H), 1.79-1.75 (m, 1H), 1.72 (s, 6H), 1.25 (d, J = 6.4 Hz,3H) 3 28

395 ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 10.65 (s, 1H), 9.31 (s, 1H), 9.09(s, 1H), 8.14 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 9.2 Hz,1H), 4.05 (s, 3H), 1.86 (s, 3H), 1.81 (s, 3H), 1.62 (s, 6H) 3 29

396 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.51 (s, 1H), 9.07 (d, J = 4.4 Hz,1H), 8.40-8.33 (m, 1H), 8.00 (s, 1H), 4.18 (s, 3H), 1.99 (s, 6H),1.93-1.82 (m, 6H) 3 30

396 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.42 (s, 1H), 9.20 (s, 1H), 8.65 (s,1H), 8.25 (s, 1H), 5.80- 5.65 (m, 1H), 4.15 (s, 3H), 2.29-2.11 (m, 2H),1.81 (d, J = 4.4 Hz, 6H), 1.14 (t, J = 7.6 Hz, 3H) 3, Intermediate 26first eluting isomer 31

396 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.29 (s, 1H), 9.06 (s, 1H), 8.51 (s,1H), 8.10 (s, 1H), 5.68- 5.53 (m, 1H), 4.03 (s, 3H), 2.19-1.95 (m, 2H),1.72-1.66 (m, 6H), 1.03 (t, J = 7.6 Hz, 3H) 3, second eluting isomer 32

399 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.38 (s, 1H), 9.30 (s, 1H), 8.38 (d,J = 6.0 Hz, 1H), 8.07 (s, 1H), 7.28 (d, J = 6.0 Hz, 1H), 4.60-4.52 (m,2H), 2.06 (s, 3H), 1.82 (s, 3H), 1.77 (s, 3H), 1.68 (s, 6H), 1.51 (t, J= 6.8 Hz, 3H) 10 33

406 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.35 (d, J = 9.6 Hz, 2H), 8.17 (t, J= 4.8 Hz, 2H), 7.22 (d, J = 8.8 Hz, 1H), 4.12 (s, 3H), 3.26 (s, 2H),1.78 (s, 6H), 1.14-1.09 (m, 2H), 0.89-0.84 (m, 2H) 3 34

406 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.47 (s, 1 H), 9.33 (s, 1 H), 8.19(s, 1 H), 8.11 (d, J = 8.8 Hz, 1 H), 7.09 (d, J = 8.8 Hz, 1 H), 4.12 (s,3 H), 3.04 (s, 2 H), 2.53 (s, 2 H), 1.84 (s, 6 H), 1.14 (s, 6H) 3 35

407 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.24 (s, 1H), 9.20-9.17 (m, 1H), 8.12(d, J = 8.8 Hz, 1H), 8.03 (s, 1H), 7.19 (d, J = 8.8 Hz, 1H), 3.21 (s,2H), 3.05 (s, 3H), 1.77 (s, 6H), 1.53 (s, 6H) 5 36

408 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.36 (s, 1H), 9.31 (s, 1H), 817 (s,1H), 8.12 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 4.11 (s, 3H),3.21 (s, 2H), 1.80 (s, 6H), 1.53 (s, 6H) 3 37

408 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.36 (s, 1H), 9.19 (s, 1H), 8.19 (s,1H), 8.14 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 4.69-4.63 (m,1H), 4.12 (s, 3H), 3.08-2.99 (m, 1H), 1.79 (d, J = 4.4 Hz, 6H), 1.51 (d,J = 7.2 Hz, 3H), 1.46 (d, J = 6.4 Hz, 3H) 3 Intermediate 17 38

408 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.35 (d, J = 0.8 Hz, 1H), 9.19 (s,1H), 8.19 (s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H),4.69- 4.61 (m, 1H), 4.12 (s, 3H), 3.07-3.00 (m, 1H), 1.79 (d, J = 4.8Hz, 6H), 1.51 (d, J = 7.2 Hz, 3H), 1.46 (d, J = 6.4 Hz, 3H) 3Intermediate 18 39

408 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.42 (s, 1H), 9.34 (s, 1H), 8.16 (s,1H), 8.13 (d, J = 8.8 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 4.93-4.89 (m,1H), 4.12 (s, 3H), 3.06-2.99 (m, 1H), 1.84 (d, J = 9.6 Hz, 6H), 1.51 (d,J = 6.8 Hz, 3H), 1.32 (d, J = 7.2 Hz, 3H) 3 first eluting isomer 40

408 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.42 (s, 1H), 9.27 (s, 1H), 8.18 (d,J = 8.8 Hz, 1H), 7.98 (s, 1H), 7.22 (d, J = 8.8 Hz, 1H), 4.95-4.92 (m,1H), 4.17 (s, 3H), 3.03- 2.96 (m, 1H), 2.06 (d, J = 13.2 Hz, 6H), 1.52(d, J = 6.8 Hz, 3H), 1.34 (d, J = 7.2 Hz, 3H) 3 second eluting isomer 41

408 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.40 (s, 1H), 9.33 (s, 1H), 8.17 (d,J = 8.8 Hz, 1H), 8.09 (s, 1H), 7.23 (d, J = 8.8 Hz, 1H), 4.84 (s, 1H),4.61 (q, J = 7.2 Hz, 2H), 3.14 (d, J = 6.8 Hz, 2H), 1.95 (d, J = 5.6 Hz,6H), 1.58 (d, J = 6.4 Hz, 3H), 1.53 (t, J = 7.2 Hz, 3H) 3, first elutingisomer 42

408 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.39 (s, 1H), 9.35 (s, 1H), 8.17 (d,J = 8.8 Hz, 1H), 8.10 (s, 1H), 7.22 (d, J = 8.8 Hz, 1H), 4.84 (s, 1H),4.63-4.57 (m, 2H), 3.14 (d, J = 7.2 Hz, 2H), 1.93 (d, J = 5.6 Hz, 6H),1.58 (d, J = 6.4 Hz, 3H), 1.53 (t, J = 7.2 Hz, 3H) 3, second elutingisomer 43

408 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.35 (s, 1H), 9.33 (s, 1H), 8.18 (s,1H), 8.14 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 4.72-4.66 (m,1H), 4.60-4.52 (m, 2H), 4.46- 4.38 (m, 1H), 3.23-3.15 (m, 1H), 1.80 (d,J = 6.0 Hz, 6H), 1.54-1.47 (m, 6H) 3, first eluting isomer 44

408 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.35 (s, 1H), 9.30 (s, 1H), 8.15 (s,1H), 8.13 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 4.73-4.66 (m,1H), 4.60-4.52 (m, 2H), 4.45- 4.40 (m, 1H), 3.22-3.13 (m, 1H), 1.83 (d,J = 6.8 Hz, 6H), 1.53-1.47 (m, 6H) 3 second eluting isomer 45

408 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.39 (d, J = 1.6 Hz, 2H), 8.23 (s,1H), 8.00 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 4.59 (d, J =7.2 Hz, 2H), 1.85 (s, 6H), 1.78 (s, 6H), 1.53 (d, J = 7.2 Hz, 3H) 4 46

408 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.43 (s, 1H), 8.14 (d, J = 8.8 Hz,1H), 8.06 (s, 1H), 7.17 (d, J = 8.4 Hz, 1H), 4.13 (s, 3H), 3.22 (s, 2H),1.92 (s, 6H), 1.54 (s, 6H) 7 47

409 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.44 (s, 1H), 9.24 (s, 1H), 8.63 (s,1H), 8.16 (s, 1H), 4.17 (s, 3H), 3.32 (s, 2H), 1.93 (s, 6H), 1.59 (s,6H) 3 48

418 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.43 (s, 1H), 8.80 (s, 1H), 7.79 (s,1H), 7.53 (s, 1H), 4.69- 4.56 (m, 1H), 4.04-3.92 (m, 1H), 3.84-3.70 (m,1H), 3.20 (s, 3H), 2.20- 2.11 (m, 2H), 2.06-2.00 (m, 1H), 1.95 (s, 6H),1.83-1.73 (m, 1H), 1.33 (d, J = 6.4 Hz, 3H) 6 49

419 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.46 (s, 1H), 8.56 (s, 1H), 7.96 (s,1H), 7.95 (s, 1H), 4.72- 4.63 (m, 1H), 4.16 (s, 3H), 4.03-3.95 (m, 1H),3.82-3.73 (m, 1H), 2.22- 2.11 (m, 2H), 2.08-2.01 (m, 1H), 1.97 (s, 6H),1.85-1.78 (m, 1H), 1.32 (d, J = 6.0 Hz, 3H) 3 50

420 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 10.64 (s, 1H), 9.18 (d, J = 0.8 Hz,1H), 8.49 (s, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.38-7.31 (m, 2H), 4.22 (t,J = 6.7 Hz, 1H), 4.06 (s, 3H), 3.21 (s, 2H), 3.15 (s, 1H), 3.09 (dt, J =10.4, 6.4 Hz, 1H), 2.98 (dt, J = 10.1, 6.7 Hz, 1H), 2.24-2.09 (m, 1H),1.84- 1.70 (m, 3H), 1.43 (s, 6H). 11 51

420 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.43 (s, 1H), 9.32 (s, 1H), 8.19 (s,1H), 8.13 (d, J = 8.8 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 5.17-5.15 (m,1H), 4.12 (s, 3H), 3.29-3.24 (m, 1H), 2.46-2.37 (m, 1H), 2.24-2.14 (m,2H), 2.12-2.01 (m, 1H), 1.99- 1.91 (m, 1H), 1.90-1.87 (m, 1H), 1.82 (d,J = 8.0 Hz, 6H) 3 Intermediate 12 52

520 ¹H NMR (400 MHz, CD₃OD): δ ppm 9.44 (s, 1H), 9.33 (s, 1H), 8.19 (s,1H), 8.14 (d, J = 8.8 Hz, 1H), 7.12 (d, J = 4.8 Hz, 1H), 5.18-5.15 (m,1H), 4.12 (s, 4H), 3.29-3.24 (m, 1H), 2.46-2.37 (m, 1H), 2.25-2.18 (m,2H), 2.11-2.02 (m, 1H), 1.98- 1.90 (m, 1H), 1.92-1.84 (m, 1H), 1.82 (d,J = 7.6 Hz, 6H) 3 Intermediate 13 53

421 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.24 (s, 1H), 9.23 (s, 1H), 8.12 (d,J = 8.8 Hz, 1H), 8.02 (s, 1H), 7.19 (d, J = 8.8 Hz, 1H), 3.59-3.51 (m,2H), 3.21 (s, 2H), 1.77 (s, 6H), 1.53 (s, 6H), 1.32 (t, J = 7.2 Hz, 3H)5 54

422 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.36 (d, J = 9.2 Hz, 2H), 8.17- 8.13(m, 2H), 7.20 (d, J = 8.4 Hz, 1H), 4.59-4.53 (m, 2H), 3.22 (s, 2H), 1.83(s, 6H), 1.53 (s, 6H), 1.52-1.48 (m, 3H) 3 55

422 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.35 (s, 1H), 9.32 (s, 1H), 8.16 (s,1H), 8.13 (d, J = 8.8 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 4.13 (s, 3H),3.07- 3.00 (m, 1H), 1.83 (d, J = 8.0 Hz, 6H), 1.54 (s, 3H), 1.45 (s,3H), 1.40 (d, J = 7.2 Hz, 3H) 3 Intermediate 21 56

422 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.36 (s, 1H), 9.31 (s, 1H), 8.15 (s,1H), 8.14 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 4.13 (s, 3H),3.07- 3.00 (m, 1H), 1.85 (d, J = 8.4 Hz, 6H), 1.54 (s, 3H), 1.45 (s,3H), 1.40 (d, J = 7.2 Hz, 3H) 3 Intermediate 20 57

422 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.36 (s, 1H), 9.18 (s, 1H), 8.17 (s,1H), 8.14 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 4.69-4.62 (m,1H), 4.59-4.53 (m, 2H), 3.07- 2.99 (m, 1H), 1.79 (d, J = 4.8 Hz, 6H),1.53-1.48 (m, 6H), 1.46 (d, J = 6.4 Hz, 3H) 3 Intermediate 17 58

422 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.37 (d, J = 0.8 Hz, 1H), 9.18 (s,1H), 8.17 (s, 1H), 8.15 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H),4.70- 4.63 (m, 1H), 4.59-4.53 (m, 2H), 3.07-2.99 (m, 1H), 1.79 (d, J =4.8 Hz, 6H), 1.53-1.49 (m, 6H), 1.46 (d, J = 6.4 Hz, 3H) 3 Intermediate18 59

422 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.43 (s, 1H), 9.32 (s, 1H), 8.17 (s,1H), 8.11 (d, J = 8.8 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 4.91-4.88 (m,1H), 4.58-4.51 (m, 2H), 3.06- 3.02 (m, 1H), 1.80 (d, J = 8.8 Hz, 6H),1.54-1.46 (m, 6H), 1.32 (d, J = 7.2 Hz, 3H) 3 Intermediate 19 firsteluting isomer 60

422 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.44 (s, 1H), 9.33 (d, J = 0.6 Hz,1H), 8.17 (s, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H),4.92- 4.88 (m, 1H), 4.58-4.51 (m, 2H), 3.06-2.99 (m, 1H), 1.80 (d, J =8.8 Hz, 6H), 1.54-1.47 (m, 6H), 1.32 (d, J = 7.2 Hz, 3H) 3 Intermediate19 second eluting isomer 61

422 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.34 (d, J = 3.2 Hz, 2H), 8.15 (s,1H), 8.13 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 4.12 (s, 3H),3.21 (s, 2H), 2.42-2.12 (m, 2H), 1.75 (s, 3H), 1.53 (s, 6H), 0.74 (t, J= 7.6 Hz, 3H) 3 first eluting isomer 62

422 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.34 (d, J = 2.4 Hz, 2H), 8.16 (s,1H), 8.13 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 4.13 (s, 3H),3.21 (s, 2H), 2.43-2.12 (m, 2H), 1.75 (s, 3H), 1.53 (s, 6H), 0.74 (t, J= 7.6 Hz, 3H) 3, second eluting isomer 63

432 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.45 (s, 1H), 9.03 (s, 1H), 8.65 (s,1H), 8.26 (s, 1H), 4.22- 4.18 (m, 1H), 4.15 (s, 3H), 1.76-1.74 (m, 9H) 364

434 8 65

434 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 10.62 (s, 1H), 9.36 (s, 1H), 9.19(s, 1H), 8.20 (s, 1H), 8.06 (d, J = 8.7 Hz, 1H), 7.37 (d, J = 8.7 Hz,1H), 4.63- 4.53 (m, 1H), 4.52- 4.43 (m, 1H), 3.03-2.92 (m, 1H), 1.66 (d,J = 2.5 Hz, 6H), 1.42 (d, J = 7.0 Hz, 3H), 1.36 (d, J = 6.5 Hz, 3H),0.88-0.79 (m, 4H). 8 Intermediate 18 66

434 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 10.61 (s, 1H), 9.38 (s, 1H), 9.19(d, J = 0.7 Hz, 1H), 8.20 (s, 1H), 8.06 (d, J = 8.7 Hz, 1H), 7.36 (d, J= 8.7 Hz, 1H), 5.73 (s, 1H), 4.63-4.52 (m, 1H), 4.52- 4.43 (m, 1H),3.03- 2.92 (m, 1H), 1.64 (d, J = 2.0 Hz, 6H), 1.39 (dd, J = 24.8, 6.8Hz, 6H), 0.85- 0.78 (m, 4H). 8 Intermediate 17 67

436 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.36 (d, J = 2.4 Hz, 2H), 8.17 (s,1H), 8.13 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 4.60-4.52 (m,2H), 3.08-3.00 (m, 1H), 1.80 (d, J = 7.2 Hz, 6H), 1.54 (s, 3H), 1.51 (t,J = 7.2 Hz, 3H), 1.45 (s, 3H), 1.40 (d, J = 7.2 Hz, 3H) 3 Intermediate20 68

436 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.34 (s, 2H), 8.17 (s, 1H), 8.12 (d,J = 8.8 Hz, 1H), 7.20 (d, J = 8.8 Hz, 1H), 4.59- 4.51 (m, 2H), 3.07-3.00(m, 1H), 1.79 (d, J = 7.2 Hz, 6H), 1.53 (s, 3H), 1.50 (t, J = 7.2 Hz,3H), 1.45 (s, 3H), 1.39 (d, J = 7.2 Hz, 3H) 3 Intermediate 21 69

436 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.36 (s, 1H), 9.32 (d, J = 0.8 Hz,1H), 8.16 (s, 1H), 8.13 (d, J = 8.4 z, 1H), 7.19 (d, J = 8.8 Hz, 1H),5.58- 5.48 (m, 1H), 3.21 (s, 2H), 1.80 (s, 6H), 1.53 (s, 6H), 1.46 (d, J= 6.0 Hz, 6H) 3 70

448 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 10.65 (s, 1H), 9.52 (s, 1H), 9.18(s, 1H), 8.21 (s, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.29 (d, J = 8.7 Hz,1H), 4.47 (td, J = 6.5, 5.6, 3.5 Hz, 1H), 2.98 (q, J = 7.1 Hz, 1H), 1.66(d, J = 2.3 Hz, 6H), 1.42 (s, 3H), 1.38- 1.27 (m, 6H), 0.88-0.79 (m,4H). 8 Intermediate 21 71

448 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 10.65 (s, 1H), 9.53 (s, 1H), 9.18(s, 1H), 8.21 (s, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.29 d, J = 8.6 Hz,1H), 4.52- 4.43 (m, 1H), 2.98 (q, J = 7.1 Hz, 1H), 2.02 (s, 1H), 1.65(d, J = 2.1 Hz, 6H), 1.42 (s, 3H), 1.38- 1.27 (m, 6H), 0.86-0.79 (m,4H). 3 Intermediate 20 72

408 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.37 (s, 1H), 9.32 (s, 1H), 8.15 (d,J = 8.8 Hz, 1H), 8.10 (s, 1H), 7.21 (d, J = 8.8 Hz, 1H), 5.48-5.35 (m,1H), 3.22 (s, 2H), 2.62- 2.51 (m, 2H), 2.34-2.22 (m, 2H), 1.96-1.91 (m,1H), 1.85 (s, 6H), 1.82- 1.74 (m, 1H), 1.53 (s, 6H) 9 73

458 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.42 (s, 1H), 9.37 (s, 1H), 8.20 (s,1H), 8.13 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 8.8 Hz, 1H), 6.52-6.18 (m,1H), 4.80-4.69 (m, 2H), 3.22 (s, 2H), 1.80 (s, 6H), 1.53 (s, 6H) 3 74

460 ¹H NMR (400 MHz, CD₃OD): δ ppm 9.27 (s, 1 H), 9.19 (s, 1 H), 8.52(s, 1 H), 8.15-8.11 (m, 2 H), 7.24 (d, J = 8.8 Hz, 1 H), 4.54-4.46 (m, 1H), 3.18 (d, J = 0.8 Hz, 2 H), 1.84 (s, 3 H), 1.65-1.56 (m, 1 H), 1.52(d, J = 7.6 Hz, 6 H), 0.94-0.86 (m, 4 H), 0.84-0.67 (m, 3 H), 0.65-0.54(m, 1 H). 3 second eluting isomer after Step 4 Example 3B 75

460 ¹H NMR (400 MHz, CD₃OD): δ ppm 10.62 (s, 1H), 9.52 (s, 1H), 9.21 (s,1H), 8.38 (s, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H),4.63- 4.54 (m, 1H), 4.53-4.43 (m, 1H), 3.02-2.92 (m, 1H), 1.64-1.60 (m,1H), 1.56 (s, 3H), 1.44 (d, J = 7.2 Hz, 3H), 1.37 (d, J = 6.4 Hz, 3H),0.88-1.80 (m, 4H), 0.62-0.53 (m, 1H), 0.50-0.38 (m, 3H). 3 secondeluting isomer after Step 4 Example 3B and Intermediate 17 76

474 ¹H NMR (400 MHz, CD₃OD): δ ppm 9.32 (s, 1H), 9.29 (s, 1H), 8.23 (s,1H), 8.15 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 4.55-4.44 (m,1H), 3.08-2.94 (m, 1H), 1.79 (s, 3H), 1.72-1.62 (m, 1H), 1.58-1.44 (m,6H), 1.40 (d, J = 7.2 Hz, 3H), 0.96-0.87 (m, 4H), 0.75- 0.49 (m, 4H) 3second eluting isomer after Step 3 Example 3B and Intermediate 20 77

476 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 10.75 (s, 1H), 9.63 (s, 1H), 9.27(s, 1H), 8.18 (s, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.30 (d, J = 8.7 Hz,1H), 5.20 (q, J = 9.0 Hz, 2H), 3.15 (s, 2H), 1.67 (s, 5H), 1.44 (s, 6H).8 78

476 ¹H NMR (400 MHz, DMSO-d₆): δ ppm 10.71 (s, 1H), 9.46 (s, 1H), 9.28(s, 1H), 8.19 (s, 1H), 8.08 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 8.7 Hz,1H), 5.20 (q, J = 9.1 Hz, 2H), 4.65- 4.53 (m, 1H), 3.05- 2.93 (m, 1H),2.04 (s, 1H), 1.65 (d, J = 2.4 Hz, 6H), 1.40 (dd, J = 25.7, 6.8 Hz, 6H).8 Intermediate 17 79

491 ¹H NMR (500 MHz, DMSO-d₆): δ ppm 10.78 (s, 1H), 9.64 (s, 1H), 9.30(d, J = 0.8 Hz, 1H), 8.21 (s, 1H), 8.08 (d, J = 8.7 Hz, 1H), 7.33 (d, J= 8.7 Hz, 1H), 5.22 (q, J = 9.1 Hz, 2H), 3.01 (q, J = 7.1 Hz, 1H), 1.68(d, J = 3.3 Hz, 7H), 1.45 (s, 3H), 1.37 (s, 3H), 1.32 (d, J = 7.1 Hz,3H). 8 Intermediate 20 80

448 ¹H NMR (400 MHz, CD₃OD): δ ppm 9.22 (s, 1H), 9.14 (s, 1H), 8.17 (s,1H), 8.11 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 4.69-4.60 (m,1H), 4.49-4.41 (m, 1H), 3.06- 2.96 (m, 1H), 2.42-2.30 (m, 1H), 2.21-2.08(m, 1H), 1.74 (s, 3H), 1.51- 1.42 (m, 6H), 0.92-0.83 (m, 4H), 0.73 (t, J= 7.2 Hz, 3H). 3 Intermediate 17 and Intermediate 33 81

82

448 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.27 (s, 1 H), 9.17 (s, 1 H), 8.22(s, 1 H), 8.14 (d, J = 8.4 Hz, 1 H), 7.30 (d, J = 8.8 Hz, 1 H),4.69-4.63 (m, 1 H), 3.06-3.00 (m, 1 H), 1.80 (d, J = 4.8 Hz, 6 H), 1.75(s, 3H), 1.51 (d, J = 7.2 Hz, 3 H), 1.46 (d, J = 6.4 Hz, 3 H), 1.33-1.28(m, 1 H), 1.08-1.05 (m, 2 H), 0.86-0.83 (m, 2 H). 3 Intermediate 17 83

462 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.30 (d, J = 20.4 Hz, 2 H), 8.20 (s,1 H), 8.13 (d, J = 8.8 Hz, 1 H), 7.22 (d, J = 8.4 Hz, 1 H), 3.06-3.01(m, 1 H), 1.83 (d, J = 8 Hz, 6 H), 1.75 (s, 3 H), 1.54 (s, 3 H), 1.45(s, 3 H), 1.40 (d, J = 7.2 Hz, 3 H), 1.29 (d, J = 4.8 Hz, 1 H),1.08-1.05 (m, 2 H), 0.86- 0.83 (m, 2 H). 3 Intermediate 20 84

462 ¹H-NMR (400 MHz, CDCl₃): δ ppm 9.30 (s, 1H), 9.19 (s, 1H), 8.23 (d,J = 9.2 Hz, 3H), 7.26 (d, J = 8.8 Hz, 1H), 4.58- 4.52 (m, 1H), 3.01-2.94(m, 1H), 2.18-2.04 (m, 2H), 1.78 (s, 3H), 1.70 (s, 3H), 1.53-1.50 (m,6H), 1.10-1.07 (m, 2H), 0.86- 0.83 (m, 2H), 0.82- 0.78 (m, 3H). 3Intermediate 38 and Intermediate 17 85

462 ¹H-NMR (400 MHz, CDCl₃): δ ppm 9.31 (s, 1H), 9.19 (s, 1H), 8.24-8.21 (m, 2H), 8.07 (s, 1H), 7.24 (d, J = 8.8 Hz, 1H), 4.58-4.52 (m, 1H),3.02-2.95 (m, 1H), 2.25- 2.00 (m, 2H), 1.78 (s, 3H), 1.69 (s, 3H), 1.53-1.50 (m, 6H), 1.10-1.07 (m, 2H), 0.86-0.83 (m, 2H), 0.81-0.77 (m, 3H). 3Intermediate 37 and Intermediate 17 86

476 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.32- 9.27 (m, 2H), 8.20 (s, 1H),8.15 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 3.03 (q, J = 7.2 Hz,1H), 2.55-2.39 (m, 1H), 2.23-2.09 (m, 1H), 1.86- 1.73 (m, 6H), 1.56 (s,3H), 1.46 (s, 3H), 1.42 (d, J = 6.8 Hz, 3H), 1.12- 1.05 (m, 2H),0.90-0.84 (m, 2H), 0.78 (t, J = 7.2 Hz, 3H) 3 Intermediate 38 andIntermediate 20 87

476 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.33 (s, 1H), 9.30 (s, 1H), 8.21-8.11 (m, 2H), 7.24 (d, J = 8.8 Hz, 1H), 3.08-2.97 (m, 1H), 2.53-2.36 (m,1H), 2.31-2.19 (m, 1H), 1.84-1.76 (m, 6H), 1.56 (s, 3H), 1.47 (s, 3H),1.43-1.38 (m, 3H), 1.12- 1.06 (m, 2H), 0.89-0.84 (m, 2H), 0.79 (t, J =7.2 Hz, 3H) 3 Intermediate 37 and Intermediate 20 88

474 ¹H-NMR (400 MHz, CDCl₃): δ ppm 9.31 (s, 1 H), 9.26 (s, 1 H), 8.51(s, 1 H), 8.24 (d, J = 8.8 Hz, 1 H), 7.95 (s, 1 H), 7.38- 7.32 (m, 1 H),4.57-4.44 (m, 1 H), 3.03-2.86 (m, 1 H), 1.79 (s, 3 H), 1.54- 1.49 (m, 11H), 1.12-1.06 (m, 2 H), 0.89-0.83 (m, 2 H), 0.70-0.60 (m, 2 H),0.52-0.43 (m, 2 H). 3 Intermediate 39 and Intermediate 17 89

474 ¹H-NMR (400 MHz, CDCl₃): δ ppm 9.31 (d, J = 2.4 Hz, 2 H), 8.55-8.50(m, 1 H), 8.23 (d, J = 8.4 Hz, 1 H), 8.07 (s, 1 H), 7.32 (d, J = 8.8 Hz,1 H), 4.60-4.44 (m, 1 H), 3.07- 2.92 (m, 1 H), 1.79 (s, 3 H), 1.62-1.61(m, 1 H), 1.54-1.48 (m, 10 H), 1.12-1.06 (m, 2 H), 0.89- 0.82 (m, 2 H),0.73-0.59 (m, 2 H), 0.55-0.42 (m, 2 H). 3 Intermediate 40 andIntermediate 17 90

488 ¹H-NMR (400 MHz, CDCl₃): δ ppm 9.38 (s, 1H), 9.32 (s, 1H), 8.52 (s,1H), 8.21 (d, J = 8.8 Hz, 1H), 8.12 (s, 1H), 7.25 (d, J = 8.4 Hz, 1H),3.02- 2.97 (m, 1H), 1.79 (m, 3H), 1.54 (s, 3H), 1.53- 1.51 (m, 1H), 1.49(s, 6H), 1.41 (d, J = 7.2 Hz, 1H), 1.11-1.07 (m, 2H), 0.87-0.83 (m, 2H),0.70- 0.59 (m, 2H), 0.54-0.43 (m, 2H). 3 Intermediate 40 andIntermediate 20 91

488 ¹H-NMR (400 MHz, CDCl₃): δ ppm 9.36 (s, 1H), 9.32 (s, 1H), 8.50 (s,1H), 8.24 (s, 1H), 8.20 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H),2.99- 2.94 (m, 1H), 1.78 (s, 3H), 1.58-1.56 (m, 1H), 1.48 (s, 3H), 1.47(s, 3H), 1.42 (d, J = 7.2 Hz, 1H), 1.10-1.07 (m, 2H), 0.91- 0.83 (m,2H), 0.65-0.61 (m, 2H), 0.51-0.42 (m, 2H). 3 Intermediate 39 andIntermediate 20 92

462 ¹H-NMR (400 MHz, CDCl₃): δ ppm 9.38 (s, 1H), 9.22 (s, 1H), 8.16-7.78 (m, 3H), 6.95 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H),4.79-4.74 (m, 1H), 2.93-2.87 (m, 1H), 2.14-2.04 (m, 2H), 1.71 (s, 3H),1.62 (s, 3H), 1.45-1.43 (m, 3H), 1.27- 1.25 (m, 3H), 1.01 (s, 2H),0.77-0.69 (m, 5H). 3 Intermediate 37 and Intermediate 41 93

462 ¹H-NMR (400 MHz, CDCl₃): δ ppm 9.34 (s, 1H), 9.23 (s, 1H), 8.18-8.12 (m, 2H), 8.01 (s, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.79-4.73 (m, 1H),2.91-2.87 (m, 1H), 2.09 (t, J = 7.6 Hz, 2H), 1.71 (s, 3H), 1.64-1.60 (m,3H), 1.44 (d, J = 6.4 Hz, 3H), 1.28 (d, J = 7.6 Hz, 3H), 1.01-0.99 (m,2H), 0.79-0.71 (m, 5H), 1.52- 1.39 (m, 2H), 1.25-1.13 (m, 1H). 3Intermediate 38 and Intermediate 41 94

474 ¹H-NMR (400 MHz, CDCl₃): δ ppm 9.43 (s, 1H), 9.23 (s, 1H), 8.43 (s,1H), 8.14 (d, J = 8.8 Hz, 1H), 7.87 (s, 1H), 7.09 (d, J = 8.8 Hz, 1H),4.75 (dd, J = 2.8, 6.4 Hz, 1H), 2.87 (dd, J = 2.8, 7.2 Hz, 1H), 1.71 (s,3H), 1.50 (s, 4H), 1.44 (d, J = 6.4 Hz, 4H), 1.28 (d, J = 7.2 Hz, 3H),1.22-1.14 (m, 1H), 1.02 (s, 2H), 0.81-0.75 (m, 2H), 0.56 (d, J = 6.0 Hz,2H), 0.45-0.37 (m, 2H) 3 Intermediate 39 and Intermediate 41 95

474 ¹H-NMR (400 MHz, CDCl₃): δ ppm 9.47 (s, 1H), 9.23 (s, 1H), 8.48-8.43 (m, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.97-7.89 (m, 1H), 7.07 (d, J =8.8 Hz, 1H), 4.75 (dd, J = 3.2, 6.4 Hz, 1H), 2.89 (dd, J = 3.2, 7.2 Hz,1H), 1.71 (s, 3H), 1.49 (s, 4H), 1.44 (d, J = 6.8 Hz, 4H), 1.25 (d, J =7.2 Hz, 3H), 1.21-1.14 (m, 1H), 1.05- 0.99 (m, 2H), 0.83-0.74 (m, 2H),0.57 (ddd, J = 4.4, 8.4, 16.8 Hz, 2H), 0.49-0.36 (m, 2H) 3 Intermediate40 and Intermediate 41 96

448 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.49 (s, 1H), 9.27 (s, 1H), 8.21 (s,1H), 8.15 (d, J = 8.8 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 4.93 (dd, J =3.2, 6.4 Hz, 1H), 4.52-4.46 (m, 1H), 3.05 (dd, J = 2.8, 7.2 Hz, 1H),2.47- 2.36 (m, 1H), 2.27-2.17 (m, 1H), 1.77 (s, 3H), 1.54 (d, J = 6.8Hz, 3H), 1.34 (d, J = 7.2 Hz, 3H), 0.94-0.89 (m, 4H), 0.76 (t, J = 7.2Hz, 3H) 3 Intermediate 33 Intermediate 41 97

420 ¹H-NMR (400 MHz, CDCl₃): δ ppm 9.31 (s, 1 H), 9.18 (s, 1 H), 8.52(s, 1 H), 8.24 (d, J = 8.4 Hz, 1 H), 8.03-7.93 (m, 1 H), 7.42 (d, J =8.8 Hz, 1 H), 4.58-4.40 (m, 2 H), 1.53 (s, 1 H), 1.50 (s, 3 H), 1.46 (d,J = 6.8 Hz, 3 H), 0.95-0.89 (m, 4 H), 0.72- 0.59 (m, 2 H), 0.52-0.41 (m,2 H). 3 Intermediate 43 98

420 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.56 (s, 1H), 9.36 (s, 1H), 8.31 (s,1H), 7.98 (d, J = 8.8 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 4.13 (s, 3H),1.76 (s, 3H), 1.75 (s, 3H), 1.73 (s, 3H), 1.72-1.68 (m, 1H), 0.64-0.56(m, 2H), 0.54- 0.41 (m, 2H). 3 Intermediate 44 99

434 ¹H-NMR (400 MHz, CDCl₃): δ ppm 9.72 (s, 1 H), 9.39 (s, 1 H), 8.48(s, 1 H), 8.12 (s, 1 H), 7.99 (d, J = 8.44 Hz, 1 H), 7.12 (d, J = 8.4Hz, 1 H), 4.27-4.08 (m, 3 H), 1.77 (s, 3 H), 1.74 (s, 3 H), 1.58-1.55(m, 4 H), 0.72- 0.59 (m, 2 H), 0.54-0.43 (m, 2 H). 3 Intermediate 43 andIntermediate 17 100

434 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.36 (s, 1H), 9.31 (s, 1H), 8.30 (s,1H), 8.15 (d, J = 8.8 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 4.70-4.61 (m,1H), 4.13 (s, 3H), 3.07-3.00 (m, 1H), 1.71 (s, 3H), 1.67-1.60 (m, 1H),1.52- 1.46 (m, 6H), 0.66-0.59 (m, 2H), 0.58-0.44 (m, 2H). 3 Intermediate44 and Intermediate 17 101

448 ¹H-NMR (400 MHz, CDCl₃): δ ppm 9.41 (s, 2 H), 8.44 (s, 1 H), 8.23(d, J = 8.4 Hz, 1 H), 8.02- 7.96 (m, 1 H), 7.30 (s, 1 H), 4.15 (s, 3 H),3.08- 2.89 (m, 1 H), 1.56 (s, 3 H), 1.55-1.53 (m, 1 H), 1.49 (d, J = 5.2Hz, 6 H), 1.45-1.41 (m, 3 H), 1.37- 1.36 (m, 1 H), 0.73-0.57 (m, 2 H),0.55-0.40 (m, 2 H). 3 Intermediate 43 and Intermediate 20 102

448 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.46 (s, 1H), 9.36 (s, 1H), 8.31 (s,1H), 8.13 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 4.13 (s, 3H),3.10- 3.02 (m, 1H), 1.73 (s, 3H), 1.70-1.61 (m, 1H), 1.54 (s, 3H), 1.46(s, 3H), 1.39 (d, J = 8.8 Hz, 3H), 0.66-0.58 (m, 2H), 0.57- 0.45 (m,2H). 3 Intermediate 44 and Intermediate 20 103

407 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.44 (s, 1H), 9.25 (s, 1H), 8.54 (s,1H), 8.13 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.19 (d, J =8.8 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 4.08 (s, 3H), 3.21 (s, 2H), 2.07(s, 6H), 1.54 (s, 6H) 4 104

411 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.61 (s, 1H), 9.42 (s, 1H), 8.12 (d,J = 8.8 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H),7.14 (d, J = 8.8 Hz, 1H), 3.24 (s, 2H), 1.87 (s, 6H), 1.55 (s, 6H) 12105

420 ¹H-NMR (400 MHz, 6d- DMSO): δ ppm 10.97- 10.89 (m, 1 H), 9.67 (s, 1H), 9.22 (s, 1 H), 8.30- 8.17 (m, 1 H), 8.02 (d, J = 8.8 Hz, 1 H),7.39-7.23 (m, 1 H), 4.53-4.45 (m, 1 H), 2.06 (d, J = 4.4 Hz, 1 H), 1.68(d, J = 1.6 Hz, 12 H), 0.90-0.74 (m, 4 H). 3 106

431 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.45 (s, 1H), 9.24 (s, 1H), 8.24 (s,1H), 8.10 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 4.52-4.40 (m,1H), 3.61 (d, J = 7.2 Hz, 2H), 3.14 (d, J = 6.8 Hz, 2H), 1.76 (s, 3H),1.67-1.61 (m, 1H), 0.91-0.88 (m, 4H), 0.75-0.45 (m, 4H). 3 secondeluting isomer after Step 3 Example 3B 107

432 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.26 (s, 1H), 8.61 (s, 1H), 8.20 (s,1H), 8.14 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 4.47-4.43 (m,1H), 4.42 (s, 2H), 1.75 (s, 6H), 1.65-1.60 (m, 2H), 1.20- 1.16 (m, 2H),0.90-0.96 (m, 4H). 3 108

432 3 second eluting isomer after Step 3 Example 3B 109

433 ¹H-NMR (400 MHz, 6d- DMSO): δ ppm 10.46 (s, 1H), 9.35-9.23 (m, 2H),8.12 (s, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 2.8 Hz, 1H), 7.35(d, J = 8.8 Hz, 1H), 4.63-4.53 (m, 1H), 3.03-2.85 (m, 2H), 1.62 (s, 6H),1.47- 1.33 (m, 6H), 0.79-0.69 (m, 2H), 0.62-0.52 (m, 2H). 5 Intermediate17 110

434 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.36 (s, 1H), 9.29 (s, 1H), 8.23 (s,1H), 7.98 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 4.53-4.42 (m,1H), 2.55-2.45 (m, 1H), 2.18- 2.08 (m, 1H), 1.77 (s, 3H), 1.76 (d, J =2.0 Hz, 6H), 0.93-0.87 (m, 4H), 0.72 (t, J = 7.2 Hz, 3H). 3 Intermediate33 111

434 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.36 (s, 1H), 9.29 (s, 1H), 8.23 (s,1H), 7.98 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 8.8 Hz, 1H), 4.52-4.44 (m,1H), 2.55-2.45 (m, 1H), 2.19- 2.08 (m, 1H), 1.79 (s, 3H), 1.76 (d, J =2.4 Hz, 6H), 0.93-0.87 (m, 4H), 0.72 (t, J = 7.6 Hz, 3H). 3 Intermediate34 112

434 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.30 (s, 1H), 8.78 (s, 1H), 8.23 (s,1H), 8.19-8.11 (m, 1H), 7.50 (d, J = 8.8 Hz, 1H), 4.51-4.44 (m, 1H),4.33 (s, 2H), 1.80 (s, 6H), 1.48 (s, 6H), 0.94-0.88 (m, 4H) 3 113

434 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.36 (s, 1H), 9.27 (s, 1H), 8.27 (s,1H), 7.99 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 4.46 (dd, J =3.2, 6.0 Hz, 1H), 2.26-2.15 (m, 2H), 1.83 (d, J = 4.4 Hz, 6H), 1.74 (s,3H), 0.95-0.85 (m, 4H), 0.77 (d, J = 7.2 Hz, 3H) 3 Intermediate 47 114

434 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.37 (s, 1H), 9.28 (d, J = 0.8 Hz,1H), 8.27 (s, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H),4.47 (dd, J = 3.2, 6.0 Hz, 1H), 2.26-2.15 (m, 2H), 1.83 (d, J = 4.4 Hz,6H), 1.75 (s, 3H), 0.95-0.86 (m, 4H), 0.78 (d, J = 7.6 Hz, 3H) 3Intermediate 46 115

439 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.37 (s, 1H), 9.17 (s, 1H), 8.40 (d,J = 6.0 Hz, 1H), 8.23 (s, 1H), 7.27 (d, J = 5.6 Hz, 1H), 5.18-5.01 (m,2H), 1.82 (s, 3H), 1.80- 1.75 (m, 9H). 3 116

444 3 117

446 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.45 (s, 1H), 9.25 (s, 1H), 8.31 (s,1H), 8.14 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 4.73-4.64 (m,1H), 4.49-4.38 (m, 2H), 3.21-3.11 (m, 1H) 1.73-1.64 (m, 4H), 1.48 (d, J= 7.2 Hz, 3H), 0.93- 0.85 (m, 4H), 0.66-0.43 (m, 4H). 3 second elutingisomer after Step 3 Example 3B and Intermediate 48 118

446 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.35 (s, 1H), 9.27 (s, 1H), 8.25 (s,1H), 8.14 (d, J = 8.8 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 4.64-4.68 (m,1H), 4.51-4.45 (m, 1H), 4.44-4.38 (m, 1H), 3.24-3.14 (m, 1H), 1.80 (s,3H), 1.71-1.62 (m, 1H), 1.47 (d, J = 7.2 Hz, 3H), 0.93-0.87 (m, 4H),0.72-0.57 (m, 3H), 0.51- 0.43 (m, 1H). 3 second eluting isomer afterStep 3 Example 3B and Intermediate 49 119

446 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.27 (s, 1H), 8.57 (s, 1H), 8.20 (s,1H), 8.15 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 4.68-4.61 (m,1H), 4.50-4.42 (m, 1H), 1.76 (s, 6H), 1.90-1.63 (m, 1H), 1.56-1.51 (m,1H), 1.37 (d, J = 6.4 Hz, 3H), 1.26-1.18 (m, 2H), 0.92- 0.86 (m, 4H). 3Intermediate 50 120

446 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.26 (s, 1H), 8.56 (s, 1H), 8.19 (s,1H), 8.14 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 4.67-4.60 (m,1H), 4.50-4.41 (m, 1H), 1.76 (s, 6H), 1.69-1.62 (m, 1H), 1.56-1.51 (m,1H), 1.37 (d, J = 6.4 Hz, 3H), 1.27-1.18 (m, 2H), 0.91- 0.86 (m, 4H). 3Intermediate 51 121

448 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.21 (s, 1H), 9.01 (s, 1H), 8.12 (d,J = 8.4 Hz, 1H), 8.05 (s, 1H), 7.30 (d, J = 8.8 Hz, 1H), 4.68-4.62 (m,1H), 3.06-2.94 (m, 1H), 2.87-2.77 (m, 1H), 2.43- 2.24 (m, 1H), 2.16-2.03(m, 1H), 1.77-1.67 (m, 3H), 1.54-1.40 (m, 6H), 0.92-0.83 (m, 2H), 0.73(t, J = 7.4 Hz, 3H), 0.67- 0.61 (m, 2H). 5 Intermediate 53 andIntermediate 17 122

447 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.22 (s, 1H), 9.05 (s, 1H), 8.13 (d,J = 8.8 Hz, 1H), 8.05 (s, 1H), 7.30 (d, J = 8.4 Hz, 1H), 4.68-4.65 (m,1H), 3.07-2.96 (m, 1H), 2.87-2.79 (m, 1H), 2.40- 2.25 (m, 1H), 2.22-2.09(m, 1H), 1.75-1.68 (m, 3H), 1.51-1.42 (m, 6H), 0.91-0.84 (m, 2H), 0.74(t, J = 7.4 Hz, 3H), 0.68- 0.62 (m, 2H). 5 Intermediate 52 andIntermediate 17, 123

447 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.25 (d, J = 4.4 Hz, 2H), 8.13 (d, J= 8.8 Hz, 1H), 8.15- 8.11 (m, 1H), 8.10 (s, 1H), 7.23 (d, J = 8.8 Hz,1H), 3.05 (q, J = 7.2 Hz, 1H), 2.85 (dd, J = 3.6, 7.2 Hz, 1H), 1.80 (d,J = 7.2 Hz, 6H), 1.55 (s, 3H), 1.46 (s, 3H), 1.40 (d, J = 7.2 Hz, 3H),0.94-0.86 (m, 2H), 0.69-0.63 (m, 2H) 5 Intermediate 20 124

447 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.33 (s, 1H), 9.05 (s, 1H), 8.15 (d,J = 8.8 Hz, 1H), 8.04 (s, 1H), 7.34 (d, J = 8.7 Hz, 1H), 4.70-4.65 (m,1H), 4.65-4.59 (m, 1H), 3.07-3.02 (m, 1H), 2.53- 2.45 (m, 2H), 2.17-2.09(m, 2H), 1.88-1.81 (m, 2H), 1.77 (d, J = 4.6 Hz, 6H), 1.53-1.49 (m, 3H),1.47 (d, J = 6.5 Hz, 3H) 5 Intermediate 17 125

448 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.34 (s, 1H), 9.13 (s, 1H), 8.10 (s,1H), 7.97 (d, J = 8.8 Hz, 1H), 7.04 (d, J = 8.8 Hz, 1H), 4.37-4.33 (m,1H), 3.18-3.14 (m, 2H), 2.22- 2.18 (m, 2H), 1.71 (s, 6H), 1.32 (s, 6H),0.81- 0.76 (m, 4H). 3 126 Intentionally Omitted 127

448 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.31 (s, 1H), 8.72 (s, 1H), 8.33-8.11 (m, 2H), 7.55 (d, J = 8.8 Hz, 1H), 4.61-4.59 (m, 1H), 4.52-4.44 (m,1H), 1.81 (d, J = 0.8 Hz, 6H), 1.55 (s, 3H), 1.48 (d, J = 6.8 Hz, 3H),1.33 (s, 3H), 0.94-0.88 (m, 4H) 3 Intermediate 56 128

448 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.32- 9.25 (m, 2H), 8.19-8.16 (m,2H), 7.28 (d, J = 8.8 Hz, 1H), 4.96-4.94 (m, 2H), 4.50 (t, J = 3.2 Hz,1H), 2.97 (s, 1H), 2.06- 1.99 (m, 1H), 1.89-1.86 (m, 6H), 1.57 (t, J =6.4 Hz, 3H), 0.95-0.90 (m, 7H). 3 Intermediate 58 129

448 ¹H-NMR (400 MHz, CD₃OD): δ ppm 8.30 (d, J = 2.4 Hz, 1H), 7.86 (d, J= 7.6 Hz, 1H), 7.57 (s, 1H), 7.06 (d, J = 2.4 Hz, 1H), 7.02 (s, 1H),6.61 (d, J = 7.6 Hz, 1H), 4.34 (s, 2H), 4.27-4.12 (m, 2H), 4.10 (s, 3H),4.06 (s, 2H), 4.00 (d, J = 2.8 Hz, 1H), 3.9 (s, 3H), 3.55- 3.48 (m, 2H),3.19-3.12 (m, 2H). 3 Intermediate 33 Intermediate 46 130

448 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.30 (s, 1H), 9.15 (s, 1H), 8.52 (s,1H), 8.16 (d, J = 8.8 Hz, 1H), 8.09 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H),4.54- 4.42 (m, 2H), 3.12-3.05 (m, 1H), 1.94 (d, J = 2.4 Hz, 6H),1.83-1.71 (m, 2H), 1.51 (d, J = 7.2 Hz, 3H), 1.08-1.05 (m, 3H),0.92-0.89 (m, 4H) 3 Intermediate 60 131

448 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.28 (s, 1H), 9.16 (s, 1H), 8.19 (s,1H), 8.15 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 4.71-4.64 (m,1H), 4.52-4.43 (m, 1H), 3.06- 2.98 (m, 1H), 2.48-2.36 (m, 1H), 2.20-2.05(m, 1H), 1.77 (s, 3H), 1.51 (d, J = 7.2 Hz, 3H), 1.46 (d, J = 6.8 Hz,3H), 0.92- 0.88 (m, 4H), 0.75 (t, J = 7.2 Hz, 3H). 3 Intermediate 34 andIntermediate 17 132

448 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.36 (s, 1H), 9.26 (s, 1H), 8.18 (s,1H), 8.14 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 4.50-4.44 (m,1H), 3.22 (s, 2H), 2.43-2.32 (m, 1H), 2.25-2.13 (m, 1H), 1.77 (s, 3H),1.53 (s, 6H), 0.93-0.87 (m, 4H), 0.76 (t, J = 7.2 Hz, 3H). 3Intermediate 33 133

448 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.35 (s, 1H), 9.26 (s, 1H), 8.16 (s,1H), 8.14 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 4.51-4.44 (m,1H), 3.22 (s, 2H), 2.46-2.35 (m, 1H), 2.25-2.15 (m, 1H), 1.79 (s, 3H),1.53 (s, 6H), 0.92-0.87 (m, 4H), 0.77 (t, J = 7.2 Hz, 3H). 3Intermediate 34 134

448 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.34 (s, 1H), 9.09 (s, 1H), 8.50 (s,1H), 8.16 (d, J = 8.4 Hz, 1H), 8.05 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H),4.55- 4.45 (m, 2H), 3.08-3.06 (m, 1H), 2.00 (d, J = 2.4 Hz, 6H),1.85-1.70 (m, 2H), 1.51 (d, J = 7.2 Hz, 3H), 1.08-1.05 (m, 3H),0.92-0.90 (m, 4H) 3 Intermediate 61 135

448 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.37 (s, 1H), 9.25 (s, 1H), 8.21 (s,1H), 8.13 (d, J = 8.8 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 3.21 (s, 2H),1.80 (s, 6H), 1.74 (s, 3H), 1.53 (s, 6H), 1.10-1.01 (m, 2H), 0.88-0.80(m, 2H). 3 136

448 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.32 (s, 1H), 8.66 (s, 1H), 8.23-8.14 (m, 2H), 7.55 (d, J = 8.8 Hz, 1H), 4.54-4.45 (m, 1H), 4.33 (s, 2H),2.50-2.37 (m, 1H), 2.23- 2.11 (m, 1H), 1.79 (s, 3H), 1.48 (s, 6H), 0.94-0.88 (m, 4H), 0.80-0.72 (m, 3H). 3 Intermediate 33 137

448 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.31 (s, 1H), 8.72 (s, 1H), 8.23-8.14 (m, 2H), 7.56 (d, J = 8.4 Hz, 1H), 4.59-4.58 (m, 1H), 4.53-4.43 (m,1H), 1.81 (s, 6H), 1.56 (s, 3H), 1.48 (d, J = 6.4 Hz, 3H), 1.33 (s, 3H),0.96- 0.88 (m, 4H) 3 Intermediate 57 138

448 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.29- 9.24 (m, 2H), 8.18-8.13 (m,2H), 7.28 (d, J = 8.8 Hz, 1H), 4.97-4.92 (m, 2H), 4.51-4.47 (m, 1H),2.98-2.94 (m, 1H), 2.04- 2.00 (m, 1H), 1.90-1.87 (m, 6H), 1.57 (t, J =6.8 Hz, 3H), 0.95-0.91 (m, 7H) 3 Intermediate 59 139

450 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.33 (s, 1H), 8.92 (s, 1H), 8.18 (d,J = 8.8 Hz, 1H), 8.01 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 4.68-4.65 (m,1H), 4.54 (m, 1H), 4.42- 4.38 (m, 1H), 4.11-4.08 (m, 1H), 3.03-3.01 (m,1H), 1.99 (s, 3H), 1.53- 1.45 (m, 6H), 0.91 (m, 4H). Example 13 1^(st)eluting isomer 140

450 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.33 (s, 1H), 8.94 (s, 1H), 8.18 (d,J = 8.8 Hz, 1H), 8.01 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 4.69-4.67 (m,1H), 4.55-4.50 (m, 1H), 4.39-4.36 (m, 1H), 4.16- 4.13 (m, 1H), 3.06-3.03(m, 1H), 1.99 (s, 3H), 1.51-1.46 (m, 6H), 0.91 (m, 4H). Example 13,2^(nd) eluting isomer 141

450 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.44 (s, 1H), 9.19 (s, 1H), 8.16-8.12 (m, 2H), 7.31 (d, J = 8.8 Hz, 1H), 5.85-5.79 (m, 1H), 5.11-5.06 (m,2H), 4.83-4.81 (m, 2H), 4.67-4.64 (m, 1H), 3.06- 2.99 (m, 1H), 1.81-1.72(m, 6H), 1.52-1.45 (m, 6H). 9 Intermediate 17 142

450 3 Intermediate 17 and Intermediate 33, isolated during the finalstep of synthesis of Compound 80 143

450 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.31 (s, 1H), 9.03 (s, 1H), 8.49 (s,1H), 8.17 (d, J = 8.8 Hz, 1H), 7.47 (s, 1H), 7.29 (d, J = 8.8 Hz, 1H),4.05- 3.98 (m, 2H), 3.20 (s, 2H), 2.46-2.36 (m, 1H), 2.31-2.17 (m, 1H),1.90- 1.80 (m, 5H), 1.53 (d, J = 2.8 Hz, 6H), 1.01 (t, J = 7.6 Hz, 3H),0.84 (t, J = 7.6 Hz, 3H). 3 Intermediate 33, isolated during the finalstep Compound 132 144

450 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.31 (s, 1H), 9.04 (s, 1H), 8.49 (s,1H), 8.17 (d, J = 8.4 Hz, 1H), 7.47 (s, 1H), 7.28 (d, J = 8.8 Hz, 1H),4.05- 3.98 (m, 2H), 3.20 (s, 2H), 2.46-2.36 (m, 1H), 2.30-2.17 (m, 1H),1.88- 1.79 (m, 5H), 1.53 (d, J = 2.0 Hz, 6H), 1.01 (t, J = 7.2 Hz, 3H),0.84 (t, J = 7.2 Hz, 3H). 3 Intermediate 34, isolated during the finalstep Compound 133 145

450 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.32 (s, 1H), 8.82 (s, 1H), 8.51 (s,1H), 8.17 (d, J = 8.8 Hz, 1H), 7.48 (s, 1H), 7.44 (d, J = 8.8 Hz, 1H),4.69- 4.64 (m, 1H), 4.05-3.97 (m, 2H), 3.04-2.95 (m, 1H), 2.47-2.35 (m,1H), 2.16-2.06 (m, 1H), 1.90- 1.81 (m, 2H), 1.76 (s, 3H), 1.471.51-1.44(m, 6H), 1.00 (t, J = 7.2 Hz, 3H), 0.80 (t, J = 7.6 Hz, 3H). 3Intermediate 17 and Intermediate 34, isolated during the final step ofsynthesis of Compound 131 146

458 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.24 (s, 1 H), 8.78-8.73 (m, 1 H),8.27 (s, 1 H), 8.13 (d, J = 8.8 Hz, 1 H), 7.49 (d, J = 8.8 Hz, 1 H),4.47-4.43 (m, 1 H), 4.41 (s, 2 H), 1.68-1.63 (m, 4 H), 1.62- 1.53 (m, 2H), 1.19-1.11 (m, 2 H), 0.92-0.86 (m, 4 H), 0.73-0.56 (m, 3 H),0.51-0.43 (m, 1 H). 3 second eluting isomer after Step 3 Example 3B 147

458 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.47 (s, 1H), 9.28 (s, 1H), 8.56 (s,1H), 8.32 (s, 1H), 8.19 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H),4.53- 4.44 (m, 1H), 3.26 (s, 2H), 1.70 (s, 3H), 1.65- 1.55 (m, 1H),1.19-1.06 (m, 2H), 0.97-0.82 (m, 6H), 0.73-0.42 (m, 4H) 3 second elutingisomer after Step 3 Example 3B 148

459 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.43 (s, 1H), 9.24 (s, 1H), 8.26 (s,1H), 8.10 (d, J = 8.8 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 4.49-4.43 (m,1H), 3.07 (s, 2H), 1.73 (s, 3H), 1.68-1.58 (m, 1H), 1.38 (s, 6H),0.92-0.86 (m, 4H), 0.73-0.49 (m, 4H) 3 second eluting isomer after Step3 Example 3B 149

459 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.24 (s, 1H), 9.16 (s, 1H), 8.22 (s,1H), 8.15 (d, J = 8.8 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 4.68-4.64 (m,1H), 3.07-2.99 (m, 1H), 2.85 (dd, J = 3.6, 6.8 Hz, 1H), 1.66 (s, 3H),1.62-1.57 (m, 1H), 1.49 (dd, J = 6.8, 11.6 Hz, 6H), 0.93- 0.87 (m, 2H),0.71-0.65 (m, 2H), 0.64-0.45 (m, 4H) 5 Intermediate 43 and Intermediate17 150

459 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.23 (s, 1H), 9.19 (s, 1H), 8.24 (s,1H), 8.18-8.12 (m, 1H), 7.37 (d, J = 8.8 Hz, 1H), 4.65 (dd, J = 4.8, 6.4Hz, 1H), 3.10-2.99 (m, 1H), 2.84 (dd, J = 3.6, 7.2 Hz, 1H), 1.69 (s,3H), 1.64- 1.57 (m, 1H), 1.49 (d, J = 6.4 Hz, 6H), 0.94-0.86 (m, 2H),0.69-0.65 (m, 2H), 0.64-0.47 (m, 4H) 5 Intermediate 44 and Intermediate17 151

460 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.30 (s, 1H), 8.97 (s, 1H), 8.34 (s,1H), 8.17 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 4.51-4.43 (m,1H), 4.33 (s, 2H), 1.69 (s, 3H), 1.67-1.61 (m, 1H), 1.48 (d, J = 4.8 Hz,6H), 0.96- 0.88 (m, 5H), 0.70-0.56 (m, 3H), 0.52-0.45 (m, 1H) 3 secondeluting isomer after Step 3 Example 3B 152

460 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.46 (s, 1 H), 9.28 (d, J = 0.8 Hz, 1H), 8.29 (s, 1 H), 8.06- 7.92 (m, 1 H), 7.30 (d, J = 8.8 Hz, 1 H),4.52-4.45 (m, 1 H), 2.20-2.14 (m, 2 H), 1.80 (s, 3 H), 1.73 (s, 3 H),0.92-0.88 (m, 5 H), 0.77-0.73 (m, 3 H), 0.67- 0.59 (m, 2 H), 0.58-0.50(m, 1 H), 0.48-0.40 (m, 1 H). 3 second eluting isomer after Step 3Example 3B and Intermediate 46 153

460 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.28 (s, 1 H), 9.17 (s, 1 H), 8.52(s, 1 H), 8.15 (d, J = 8.4 Hz, 1 H), 8.11 (s, 1 H), 7.25 (d, J = 8.4 Hz,1 H), 4.57-4.46 (m, 1 H), 3.19 (d, J = 2.4 Hz, 2 H), 1.86 (s, 3 H),1.65-1.57 (m, 1 H), 1.52 (d, J = 8.4 Hz, 6 H), 0.94-0.86 (m, 4 H),0.85-0.70 (m, 3 H), 0.66- 0.55 (m, 1 H). 3 first eluting isomer afterStep 3 Example 3B 154

460 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.57 (s, 1 H), 9.24 (s, 1 H), 8.29(s, 1 H), 8.12 (d, J = 8.4 Hz, 1 H), 7.18 (d, J = 8.8 Hz, 1 H),4.64-4.54 (m, 1 H), 4.44-4.41 (m, 1 H), 3.05-2.96 (m, 1 H), 1.77- 1.65(m, 4 H), 1.50 (d, J = 6.4 Hz, 3 H), 1.32 (d, J = 7.2 Hz, 3 H),0.95-0.82 (m, 4 H), 0.68-0.44 (m, 4 H). 3 second eluting isomer afterStep 3 Example 3B and Intermediate 41 155

460 ¹H-NMR (400 MHz, 6d- DMSO): δ ppm 10.69 (s, 1 H), 9.80 (s, 1 H),9.19 (s, 1 H), 8.40-8.36 (m, 1 H), 8.06 (d, J = 8.8 Hz, 1 H), 7.28 (s, 1H), 4.92- 4.85 (m, 1 H), 4.53-4.46 (m, 1 H), 3.02-2.95 (m, 1 H), 1.61(s, 4 H), 1.41 (d, J = 6.4 Hz, 3 H), 1.19 (d, J = 7.2 Hz, 3 H), 0.86-0.82 (m, 4 H), 0.64-0.39 (m, 4 H). 3 second eluting isomer after Step 3Example 3B and Intermediate 42 156

462 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.39 (s, 1H), 9.28 (s, 1H), 8.21 (s,1H), 8.14 (d, J = 8.7 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 4.55-4.43 (m,1H), 3.05 (q, J = 7.1 Hz, 1H), 2.44-2.32 (m, 1H), 2.26- 2.16 (m, 1H),1.76 (s, 3H), 1.56 (s, 3H), 1.47 (s, 3H), 1.41 (d, J = 7.2 Hz, 3H),0.95-0.88 (m, 4H), 0.76 (t, J = 7.5 Hz, 3H). 3 Intermediate 20 andIntermediate 33 157

462 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.32 (s, 1H), 8.64 (s, 1H), 8.26-8.11 (m, 2H), 7.58 (d, J = 8.8 Hz, 1H), 4.61-4.57 (m, 1H), 4.53-4.46 (m,1H), 2.46-2.33 (m, 1H), 2.20-2.08 (m, 1H), 1.77 (s, 3H), 1.54 (s, 3H),1.48 (d, J = 6.8 Hz, 3H), 1.33 (s, 3H), 0.97-0.87 (m, 4H), 0.80-0.70 (m,3H) 3 Intermediate 33 and Intermediate 56 158

462 ¹H-NMR (400 MHz, 6d- DMSO): δ ppm 10.80 (s, 1H), 9.38 (s, 1H), 9.14(s, 2H), 8.83 (s, 1H), 8.17- 8.13 (m, 2H), 7.41-7.39 (m, 1H), 4.11 (s,3H), 3.09 (s, 2H), 2.52 (s, 1H), 2.12-2.05 (m, 2H), 1.99 (s, 5H),1.92-1.87 (m, 2H), 1.69-1.58 (m, 2H), 1.45 (s, 6H). 14 159

464 ¹H-NMR (400 MHz,CD₃OD): δ ppm 9.35 (s, 1H), 9.15 (s, 1H), 8.17 (s,1H), 8.14 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 5.82-5.75 (m,1H), 4.70-4.65 (m, 1H), 4.16-3.99 (m, 3H), 3.98-3.91 (m, 1H), 3.08- 2.97(m, 1H), 2.45-2.34 (m, 1H), 2.33-2.23 (m, 1H), 1.82 (d, J = 4.8 Hz, 6H),1.50 (d, J = 7.2 Hz, 3H), 1.46 (d, J = 6.4 Hz, 3H). 3 Intermediate 17and Intermediate 36h 160

464 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.38 (s, 1H), 9.11 (s, 1H), 8.18-8.11 (m, 2H), 7.32 (d, J = 8.8 Hz, 1H), 5.83-5.75 (m, 1H), 4.71-4.62 (m,1H), 4.13-4.00 (m, 3H), 3.99-3.89 (m, 1H), 3.06- 2.98 (m, 1H), 2.45-2.34(m, 1H), 2.33-2.25 (m, 1H), 1.86 (d, J = 5.6 Hz, 6H), 1.51 (d, J = 7.2Hz, 3H), 1.46 (d, J = 6.4 Hz, 3H). 3 Intermediate 17 and Intermediate36g 161

466 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.30 (s, 1H), 8.98 (s, 1H), 8.08-8.04 (m, 1H), 7.99 (s, 1H), 7.25 (d, J = 8.8 Hz, 1H), 5.55 (dt, J = 3.2,7.2 Hz, 1H), 5.35-5.31 (m, 1H), 5.21-5.17 (m, 1H), 4.59-4.54 (m, 1H),2.95- 2.91 (m, 1H), 2.74-2.65 (m, 2H), 2.63-2.55 (m, 2H), 1.79 (d, J =5.4 Hz, 6H), 1.41 (d, J = 7.2 Hz, 3H), 1.36 (d, J = 6.6 Hz, 3H) 3Intermediate 17 and Intermediate 36i 162

466 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.45 (s, 1H), 9.09 (s, 1H), 8.17 (d,J = 8.8 Hz, 1H), 8.08 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 4.85-4.80 (m,2H), 4.71-4.64 (m, 1H), 3.07-2.989 (m, 1H), 1.91 (d, J = 5.4 Hz, 6H),1.52 (d, J = 5.6 Hz, 3H), 1.46 (d, J = 7.6 Hz, 3H), 1.24- 1.14 (m, 2H),1.00-0.92 (m, 2H) 3 Intermediate 17 163

466 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.38 (s, 1H), 9.17 (s, 1H), 8.24-8.03 (m, 2H), 7.31 (d, J = 8.8 Hz, 1H), 5.08-4.93 (m, 2H), 4.70-4.61 (m,1H), 3.16-3.07 (m, 2H), 3.05-2.98 (m, 1H), 2.56- 2.32 (m, 2H), 1.79 (d,J = 4.8 Hz, 6H), 1.50 (d, J = 7.2 Hz, 3H), 1.45 (d, J = 6.4 Hz, 3H). 3Intermediate 17 and Intermediate 36j 164

472 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.39 (s, 1 H), 9.35 (s, 1 H), 8.17(s, 1 H), 8.14 (d, J = 8.8 Hz, 1 H), 7.22-7.16 (m, 1 H), 6.32-5.98 (m, 1H), 5.77-5.59 (m, 1 H), 3.21 (s, 2 H), 1.83 (s, 3 H), 1.53 (s, 6 H),1.28 (s, 6 H). 3 1^(st) eluting isomer from SFC (column: DaicelChiralpak IG (250 mm × 50 mm, 10 um); mobile phase: [EtOH with 0.1%NH₄OH] 165

472 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.39 (s, 1 H), 9.35 (s, 1 H), 8.18(s, 1 H), 8.14 (d, J = 8.8 Hz, 1 H), 7.23-7.17 (m, 1 H), 6.33-6.00 (m, 1H), 5.76-5.63 (m, 1 H), 3.22 (s, 2 H), 1.83 (s, 3 H), 1.56-1.51 (m, 6H),1.28 (s, 6 H). 3 2^(nd) eluting isomer from SFC (column: DaicelChiralpak IG (250 mm × 50 mm, 10 um); mobile phase: [EtOH with 0.1%NH₄OH] 166

472 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.46 (d, J = 6 Hz, 1H), 8.97 (s, 1H),8.21-8.17 (m, 1H), 7.98 (s, 1H), 7.40 (d, J = 8.8 Hz, 1H), 4.82-4.76 (m,2H), 4.71-4.65 (m, 1H), 3.04-2.98 (m, 1H), 2.05 (d, J = 10.4 Hz, 6H),1.90-1.78 (m, 3H), 1.52 (d, J = 7.2 Hz, 3H), 1.47 (d, J = 6.4 Hz, 3H). 3Intermediate 17 167

472 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.27 (s, 1H), 8.85 (s, 1H), 8.35 (s,1H), 8.14 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 4.67-4.60 (m,1H), 4.49-4.42 (m, 1H), 1.73- 1.54 (m, 6H), 1.37 (d, J = 6.8 Hz, 3H),1.24-1.14 (m, 2H), 0.93-0.85 (m, 4H), 0.67-0.54 (m, 3H), 0.51-0.42 (m,1H). 3 second eluting isomer after Step Example 3B and Intermediate 50168

474 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.33 (s, 1 H), 9.27 (s, 1 H), 8.52(s, 1 H), 8.15 (d, J = 8.8 Hz, 1 H), 8.06 (s, 1 H), 7.22 (d, J = 8.4 Hz,1 H), 4.54-4.45 (m, 1 H), 3.70- 3.58 (m, 1 H), 3.23 (s, 2 H), 2.24-1.91(m, 3 H), 1.87 (s, 3 H), 1.84-1.60 (m, 3 H), 1.54 (s, 6 H), 0.95-0.84(m, 4 H). 3 Intermediate 63 169

474 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.35 (s, 1 H), 9.27 (s, 1 H), 8.51(d, J = 1.2 Hz, 1 H), 8.16 (d, J = 8.8 Hz, 1 H), 8.07 (s, 1 H), 7.22 (d,J = 8.8 Hz, 1 H), 4.54-4.44 (m, 1 H), 3.70-3.59 (m, 1 H), 3.24 (s, 2 H),2.25-1.90 (m, 3 H), 1.86 (s, 3 H), 1.84-1.60 (m, 3 H), 1.54 (s, 6 H),0.89 (s, 4 H). 3 Intermediate 64 170

474 ¹H-NMR (400 MHz, CDCl₃): δ ppm 9.31 (d, J = 2.0 Hz, 2H), 8.26 (d, J= 8.4 Hz, 1H), 8.12 (s, 1H), 8.02 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H),4.63- 4.46 (m, 2H), 3.37-3.19 (m, 1H), 3.00 (quin, J = 6.8 Hz, 1H),2.04-1.93 (m, 4H), 1.77 (d, J = 5.6 Hz, 1H), 1.65 (s, 1H), 1.59 (s, 3H),1.58-1.53 (m, 6H), 0.95-0.88 (m, 4H). 3 Intermediate 63 and Intermediate17 171

474 ¹H-NMR (400 MHz, 6d- DMSO): δ ppm 10.56 (s, 1H), 9.33 (s, 1H), 9.23(s, 1H), 8.40 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.8 Hz,1H), 4.60- 4.53 (m, 1H), 4.53-4.47 (m, 1H), 1.63-1.57 (m, 1H), 1.51 (d,J = 18.4 Hz, 6H), 1.36 (d, J = 6.4 Hz, 3H), 1.22 (s, 3H), 0.89- 0.80 (m,4H), 0.63-0.53 (m, 1H), 0.52-0.41 (m, 3H) 3 Intermediate 56 and secondeluting isomer after Step 4 Example 3B 172

476 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.45- 9.34 (m, 2H), 8.23 (s, 1H),8.03 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 5.17-5.10 (m, 2H),2.27-2.15 (m, 2H), 1.90 (d, J = 6.2 Hz, 6H), 1.75 (s, 3H), 0.81-0.77 (m,3H) 3 Intermediate 47 173

476 ¹H-NMR (400 MHz, 6d- DMSO): δ ppm 11.04 (s, 1H), 9.61 (s, 1H), 9.32(s, 1H), 8.23 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.8 Hz,1H), 5.28- 5.16 (m, 2 H), 2.25-2.06 (m, 2H), 1.71-1.64 (m, 9H), 0.61 (t,J = 7.2 Hz, 3H). 3 1^(st) eluting isomer from SFC (column: DaicelChiralpak AD-H (250 mm × 30 mm, 5 um); mobile phase: [EtOH with 0.1%NH₄OH] 174

476 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.45- 9.34 (m, 2H), 8.23 (s, 1H),8.03 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 5.17-5.10 (m, 2H),2.27-2.15 (m, 2H), 1.90 (d, J = 6.2 Hz, 6H), 1.75 (s, 3H), 0.81-0.77 (m,3H) 3 Intermediate 46 175

476 ¹H-NMR (400 MHz, 6d- DMSO): δ ppm 11.11 (s, 1H), 9.40 (s, 1H), 9.35(s, 1H), 8.17 (s, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 8.8 Hz,1H), 5.30- 5.18 (m, 2H), 2.35-2.08 (m, 2H), 1.76 (s, 3H), 1.68 (d, J =5.6 Hz, 6H), 0.65 (t, J = 7.2 Hz, 3H). 3 2^(nd) eluting isomer from SFC(column: Daicel Chiralpak AD-H (250 mm × 30 mm, 5 um); mobile phase:[EtOH with 0.1% NH₄OH] 176

477 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.38 (s, 1H), 9.28 (s, 1H), 8.33 (d,J = 5.6 Hz, 1H), 7.12 (d, J = 86.0 Hz, 1H), 5.14-5.07 (m, 2H), 4.23 (s,1H), 3.41-3.35 (m, 1H), 2.05-1.63 (m, 14H). 3 Intermediate 65 177

478 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.91 (s, 1H), 9.23 (s, 1H), 8.18-8.07 (m, 1H), 8.02 (s, 1H), 7.27-7.14 (m, 1H), 4.51-4.36 (m, 1H), 3.55-3.41 (m, 2H), 3.26 (s, 2H), 2.47-2.37 (m, 2H), 1.82-1.66 (m, 6H), 1.54(s, 6H), 0.89 (s, 4H). 15 178

484 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.42 (d, J = 0.6 Hz, 1H), 9.15 (s,1H), 8.20-8.13 (m, 2H), 7.35 (d, J = 8.7 Hz, 1H), 5.44-5.34 (m, 1H),4.72- 4.65 (m, 1H), 3.29-3.19 (m, 2H), 3.08-3.00 (m, 1H), 2.96-2.84 (m,2H), 1.88 (d, J = 5.5 Hz, 6H), 1.53 (d, J = 7.2 Hz, 3H), 1.48 (d, J =6.6 Hz, 3H) 3 Intermediate 17 179

490 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.40 (s, 1H), 9.24 (s, 1H), 8.19 (d,J = 8.8 Hz, 1H), 8.01 (d, J = 1.2 Hz, 1H), 7.26 (d, J = 8.6 Hz, 1H),6.18- 6.10 (m, 1H), 3.22 (s, 2H), 2.07 (s, 6H), 1.63 (d, J = 6.4 Hz,3H), 1.54 (s, 6H) 3 2^(nd) isomer to elute from SFC Column: ChiralpakIG-3 Mobile Phase: [EtOH + 0.05% Diethylamine] in CO₂ 180

490 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.40 (s, 1H), 9.24 (s, 1H), 8.19 (d,J = 8.8 Hz, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H),6.18- 6.10 (m, 1H), 3.22 (s, 2H), 2.07 (s, 6H), 1.63 (d, J = 6.4 Hz,3H), 1.54 (s, 6H) 3 1^(st) isomer to elute from SFC Column: ChiralpakIG-3 Mobile Phase: [EtOH + 0.05% Diethylamine] in CO₂ 181

490 3 1^(st) isomer to elute from SFC Column: ChiralPak IC-H 21 × 250 mmMobile Phase: 25% 2- Propanol + 0.5% Diethylamine in CO₂ andIntermediate 17 182

490 3 2nd isomer to elute from SFC Column: ChiralPak IC-H 21 × 250 mmMobile Phase: 25% 2- Propanol + 0.5% Diethylamine in CO₂ andIntermediate 17 183

490 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.76 (s, 1H), 9.23 (s, 1H), 8.12 (d,J = 8.8 Hz, 1H), 7.99 (s, 1H), 7.24 (d, J = 8.8 Hz, 1H), 4.57-4.51 (m,2H), 4.49-4.44 (m, 3H), 3.77-3.69 (m, 1H), 3.26 (s, 2H), 1.65 (s, 6H),1.55 (s, 6H), 0.91-0.88 (m, 4H). 14 184

464 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.24 (s, 1H), 9.20 (s, 1H), 8.19 (s,1H), 8.13 (d, J = 8.8 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 4.69-4.63 (m,1H), 4.45-4.43 (m, 1H), 3.97- 3.95 (m, 1H), 3.83-3.81 (m, 1H), 3.35 (s,3H), 3.06-2.99 (m, 1H), 1.74 (s, 3H), 1.52-1.46 (m, 6H), 0.93-0.87 (m,4H) First eluting isomer described in Example 16 and using Intermediate17 185

474 ¹H-NMR (400 MHz, CDCl₃): δ ppm 9.33 (s, 1H), 9.18 (s, 1H), 8.52 (s,1H), 8.23 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.8 Hz, 1H), 4.25 (s, 2H),1.78 (s, 3H), 1.55-1.52 (m, 1H), 1.50 (s, 3H), 1.45 (d, J = 1.6 Hz, 6H),1.10-1.07 (m, 2H), 0.88-0.83 (m, 2H), 0.71-0.60 (m, 2H), 0.51-0.41 (m,2H). 3 Intermediate 39 186

462 ¹H-NMR (400 MHz, CDCl₃): δ ppm 9.25 (s, 1H), 8.94 (s, 1H), 8.17-8.15 (m, 2H), 7.82 (s, 1H), 7.28 (d, J = 8.8 Hz, 1H), 4.45-4.40 (m, 1H),1.71 (s, 3H), 1.66 (s, 6H), 1.44 (s, 3H), 1.39 (d, J = 6.8 Hz, 3H), 1.22(s, 3H), 1.03-0.99 (m, 2H), 0.79- 0.75 (m, 2H). 3 Intermediate 56 187

460 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.25 (s, 1H), 8.47 (s, 1H), 8.15 (s,1H), 8.13 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 4.62 (q, J =6.4 Hz, 1H), 4.49-4.42 (m, 1H), 2.33-2.22 (m, 1H), 2.15- 2.05 (m, 1H),1.72 (s, 3H), 1.67-1.61 (m, 1H), 1.54-1.48 (m, 1H), 1.37 (d, J = 6.8 Hz,3H), 1.25- 1.15 (m, 2H), 0.92-0.86 m, 4H), 0.74 (d, J = 7.6 Hz, 3H) 3Intermediate 50 and Intermediate 33 188

438 ¹H-NMR (400 MHz, CDCl₃): δ ppm 9.38 (s, 1H), 9.27 (s, 1H), 8.24 (d,J = 8.4 Hz, 1H), 8.14 (s, 1H), 8.04 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H),4.58- 4.51 (m, 1H), 4.13 (s, 3H), 3.89 (d, J = 8.8 Hz, 1H), 3.59 (d, J =8.8 Hz, 1H), 3.43 (s, 3H), 3.02- 2.96 (m, 1H), 1.70 (s, 3H), 1.55-1.51(m, 6H). 16 Intermediate 67 and Intermediate 17 189

478 ¹H-NMR (400 MHz, CDCl₃): δ ppm 9.40 (s, 1H), 9.30 (s, 1H), 8.24 (t,J = 5.2 Hz, 2H), 8.04 (s, 1H), 7.21 (d, J = 8.8 Hz, 1H), 4.54-4.49 (m,1H), 3.91 (d, J = 8.8 Hz, 1H), 3.63 (d, J = 9.2 Hz, 1H), 3.44 (s, 3H),3.04-2.98 (m, 1H), 1.73 (s, 3H), 1.51 (d, J = 8.4 Hz, 6H), 1.45 (d, J =7.2 Hz, 3H), 0.97-0.89 (m, 4H). 16 Intermediate 69 and Intermediate 20190

464 ¹H-NMR (400 MHz, CDCl₃): δ ppm 9.52 (s, 1 H), 9.28 (s, 1 H), 8.25-8.19 (m, 2 H), 7.93-7.89 (m, 1 H), 7.10 (d, J = 8.8 Hz, 1 H), 4.87-4.81(m, 1 H), 4.55-4.47 (m, 1 H), 3.90 (d, J = 8.8 Hz, 1 H), 3.64 (d, J =8.8 Hz, 1 H), 3.43 (s, 3 H), 3.03-2.93 (m, 1 H), 1.73 (s, 3 H), 1.52 (d,J = 6.4 Hz, 3 H), 1.36 (d, J = 7.2 Hz, 3 H), 0.96-0.85 (m, 4 H). 16Intermediate 69 and Intermediate 41 191

462 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.27 (d, J = 0.8 Hz, 1 H), 8.84- 8.76(m, 1 H), 8.21 (s, 1 H), 8.14 (d, J = 8.8 Hz, 1 H), 7.28 (d, J = 8.8 Hz,1 H), 4.60-4.54 (m, 1 H), 3.23-3.14 (m, 1 H), 2.13- 2.00 (m, 2 H), 1.76(s, 3 H), 1.56-1.47 (m, 6 H), 1.44 (s, 3 H), 1.10-1.05 (m, 2 H),1.05-1.00 (m, 3 H), 0.89-0.82 (m, 2 H). 17 Intermediate 79 andIntermediate 20 192

438 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.46 (s, 1H), 9.31 (d, J = 0.8 Hz,1H), 8.20 (s, 1H), 8.12 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H),4.93 (d, J = 3.2, 6.5 Hz, 1H), 4.13 (s, 3H), 3.97-3.88 (m, 2H), 3.38 (s,3H), 3.04 (d, J = 2.8, 7.2 Hz, 1H), 1.77 (s, 3H), 1.54 (d, J = 6.4 Hz,3H), 1.34 (d, J = 7.2 Hz, 3H) 16 Intermediate 67 and Intermediate 41 193

490 ¹H-NMR (400 MHz,CD₃OD): δ ppm 9.40 (s, 1H), 9.01 (s, 1H), 8.16 (d, J= 8.8 Hz, 1H), 8.09 (s, 1H), 7.41 (d, J = 8.8 Hz, 1H), 5.64-5.53 (m,1H), 4.70-4.55 (m, 2H), 3.06-2.94 (m, 1H), 2.65-2.45 (m, 4H), 1.80 (s,3H), 1.65-1.56 (m, 1H), 1.51-1.44 (m, 6H), 0.79-0.48 (m, 4H). Example 18194

407 ¹H-NMR (400 MHz, CD3OD): δ ppm 9.46 (d, J = 1.6 Hz, 1H), 8.71- 8.67(m, 1H), 8.18-8.15 (m, 1H), 7.82-7.78 (m, 1H), 7.27 (d, J = 8.8 Hz, 1H),7.04-7.01 (m, 1H), 4.96-4.92 (m, 1H), 4.59- 4.52 (m, 1H), 4.04 (s, 3H),3.14-3.06 (m, 1H), 2.25-2.12 (m, 2H), 1.60 (d, J = 6.8 Hz, 3H), 1.55 (d,J = 6.4 Hz, 3H), 1.01- 0.97 (m, 3H). 17 Intermediate 73 and Intermediate17 195

460 ¹H-NMR (400 MHz, CDCl₃): δ ppm 9.29 (s, 1H), 8.93 (s, 1H), 8.24-8.21 (m, 2H), 8.01 (s, 1H), 7.27-7.25 (m, 1H), 4.51-4.46 (m, 1H), 1.74(s, 6H), 1.63 (s, 2H), 1.42 (s, 6H), 1.11 (s, 2H), 0.95-0.90 (m, 4H). 3196

474 3 Intermediate 33 197

464 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.37 (s, 1H), 9.22 (s, 1H), 8.18-8.11 (m, 2H), 7.32 (d, J = 8.8 Hz, 1H), 5.03 (d, J = 6.8 Hz, 2H), 4.71(d, J = 6.8 Hz, 2H), 4.69-4.62 (m, 1H), 3.10-2.98 (m, 1H), 1.94 (s, 3H),1.79 (d, J = 5.2 Hz, 6H), 1.52- 1.45 (m, 6H). 9 Intermediate 17 198

478 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.40- 7.30 (m, 2H), 8.19-8.09 (m,2H), 7.22 (d, J = 8.8 Hz, 1H), 5.03 (d, J = 7.2 Hz, 2H), 4.71 (d, J =7.2 1H), 1.94 (s, 3H), 1.80 (d, J = 7.2 Hz, 6H), 1.54 (s, 3H), 1.45 (s,3H), 1.41 (d, J = 7.2 Hz, 3H). 9 Intermediate 20 199

474 ¹H-NMR (400 MHz, CDCl₃): δ ppm 9.30 (s, 1H), 8.84 (s, 1H), 8.24-8.22 (m, 2H), 8.04 (s, 1H), 7.30 (s, 1H), 1.77 (s, 9H), 1.60 (s, 1H),1.41 (s, 6H), 1.08 (s, 2H), 1.06 (s, 2H), 0.89-0.82 (m, 2H). 3 200

464 ¹H-NMR (400 MHz, CDCl₃): δ ppm 9.46 (s, 1 H), 9.28 (d, J = 0.8 Hz, 1H), 8.29-8.17 (m, 2 H), 7.98 (s, 1 H), 7.16 (d, J = 8.4 Hz, 1 H),4.55-4.47 (m, 1 H), 3.93 (d, J = 9.2 Hz, 1 H), 3.61 (d, J = 8.8 Hz, 1H), 3.44 (s, 3 H), 3.16 (s, 2 H), 1.72 (s, 3 H), 1.55 (s, 6 H), 0.95-0.87 (m, 4 H). 16 Intermediate 69 201

452 ¹H-NMR (400 MHz, 6d- DMSO): δ ppm 10.88 (s, 1H), 9.37 (s, 1H), 8.96(s, 1H), 8.90 (s, 2H), 8.13 (d, J = 8.8 Hz, 1H), 7.99 (s, 1H), 7.47 (d,J = 8.8 Hz, 1H), 4.10 (s, 3H), 4.06-4.01 (m, 2H), 3.31 (s, 3H),2.95-2.90 (m, 1H), 1.87 (s, 3H), 1.45 (s, 3H), 1.39 (s, 3H), 1.29 (d, J= 7.2 Hz, 3H). 16 Intermediate 67 and Intermediate 20 202

392 17 Intermediate 71 and Intermediate 203

408 ¹H NMR (500 MHz, DMSO) δ 10.63 (s, 1H), 9.23 (s, 1H), 8.79 (s, 1H),8.11 (s, 1H), 8.03 (d, J = 8.7 Hz, 1H), 7.27 (d, J = 8.7 Hz, 1H),4.51-4.42 (m, 1H), 4.25 (t, J = 6.4 Hz, 1H), 3.99 (s, 3H), 2.99 (p, J =7.0 Hz, 1H), 2.22 (s, 2H), 1.76 (dq, J = 13.7, 6.9 Hz, 1H), 1.67 (dq, J= 14.0, 7.2 Hz, 1H), 1.43 (d, J = 7.0 Hz, 3H), 1.38 (d, J = 6.3 Hz, 3H),0.83 (t, J = 7.3 Hz, 3H). 17 Intermediate 76 and Intermediate 17 204

422 ¹H NMR (500 MHz, DMSO) δ 10.71 (s, 1H), 9.30 (d, J = 1.9 Hz, 1H),8.91 (s, 1H), 8.17 (d, J = 1.9 Hz, 1H), 8.08 (dd, J = 8.7, 1.9 Hz, 1H),7.34 (dd, J = 8.6, 2.0 Hz, 1H), 4.30 (t, J = 6.5 Hz, 1H), 4.06 (d, J =1.9 Hz, 3H), 3.15 (ddd, J = 13.9, 8.9, 5.1 Hz, 1H), 1.91-1.81 (m, 1H),1.76 (dq, J = 13.9, 7.5, 7.1 Hz, 1H), 1.45 (d, J = 1.9 Hz, 3H), 1.41(dd, J = 7.1, 1.9 Hz, 3H), 1.35 (d, J = 1.9 Hz, 3H), 0.91 (td, J = 7.4,1.9 Hz, 3H). 17 Intermediate 76 and Intermediate 20 205

422 ¹H-NMR (400 MHz, 6d- DMSO): δ ppm 10.64 (s, 1H), 9.50 (s, 1H), 9.43(s, 1H), 8.45 (s, 1H), 8.09 (d, J = 8.7 Hz, 1H), 7.41 (d, J = 8.8 Hz,1H), 4.67- 4.57 (m, 1H), 3.85-3.79 (m, 1H), 3.78-3.72 (m, 1H), 3.25 (s,3H), 3.05- 2.95 (m, 1H), 2.90 (s, 3H), 1.63 (s, 3H), 1.46 (d, J = 7.2Hz, 3H), 1.39 (d, J = 6.8 Hz, 3H) 16 Intermediate 17 and Intermediate 70206

436 ¹H-NMR (400 MHz, 6d- DMSO): δ ppm 10.68 (s, 1H), 9.63 (s, 1H), 9.43(s, 1H), 8.46 (s, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.33 (d, J = 8.8 Hz,1H), 3.81 (s, 2H), 3.26 (s, 3H), 3.07-2.94 (m, 1H), 2.90 (s, 3H), 1.65(s, 3H), 1.46 (s, 3H), 1.38 (s, 3H), 1.33 (d, J = 7.2 Hz, 3H) 16Intermediate 20 and Intermediate 70 207

433 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.75- 9.52 (m, 1 H), 8.34 (d, J = 8.8Hz, 1 H), 8.25 (s, 1 H), 8.04 (d, J = 8.4 Hz, 1 H), 7.22 (d, J = 2.0 Hz,1 H), 7.19 (d, J = 0.8 Hz, 1 H), 5.03-4.94 (m, 1 H), 4.17 (s, 3 H),2.30-2.09 (m, 2 H), 1.65-1.56 (m, 2 H), 1.55-1.48 (m, 2 H), 1.46 (s, 6H), 1.04-0.97 (m, 3 H). 17 Interemediate 73 208

438 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.36 (s, 1H), 8.90 (s, 1H), 8.24-8.10 (m, 2H), 7.26 (d, J = 8.8 Hz, 1H), 4.95-4.91 (m, 1H), 4.15 (s, 3H),3.85-3.80 (m, 1H), 3.66- 3.57 (m, 1H), 3.47 (s, 3H), 3.25-3.19 (m, 1H),1.55-1.43 (m, 9H). 16 Intermediate 81 and Intermediate 20 209

425 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.37 (s, 1H), 9.00 (s, 1H), 8.08 (d,J = 8.8 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H),7.18 (d, J = 8.8 Hz, 1H), 4.66- 4.59 (m, 1H), 3.13 (q, J = 7.2 Hz, 1H),2.02-1.83 (m, 2H), 1.52-1.48 (m, 6H), 1.44 (s, 3H), 1.01- 0.94 (m, 3H)17 Intermediate 77 and Intermediate 20 210

406 ¹H-NMR (400 MHz, CD₃OD): δ ppm 9.51 (s, 1 1 H), 8.87 (s, 1 H), 8.52(s, 1 H), 8.47 (s, 1 H), 8.15 (d, J = 8.8 Hz, 1 H), 7.30 (d, J = 8.8 Hz,1 H), 4.80-4.76 (m, 1 H), 3.23- 3.15 (m, 1 H), 3.00 (s, 3 H), 2.19-2.02(m, 2 H), 1.57-1.48 (m, 6 H), 1.45 (s, 3 H), 1.10-0.96 (m, 3 H),0.77-0.76 (m, 1 H). 17 Intermediate 77 and Intermediate 20

Included in the present teachings are pharmaceutically acceptable saltsof the compounds disclosed herein (including compounds disclosed inTable 1 and Exemplification) as well as the corresponding neutral form.

Another embodiment of the disclosure a deuterated is a compounddisclosed herein, including a compound of Formulas I-IV, V(A)-V(C),VI(A)-VI(C), VII-IX, VII(A)-IX(A) and X or a compound in Table 1 andexemplification or a pharmaceutically acceptable salt of any of theforegoing, in which one or more hydrogen atoms is replaced withdeuterium. The deuterium enrichment at any one of the sites wherehydrogen has been replaced by deuterium is at least 50%, 75%, 85%, 90%,95%, 98% or 99%. Deuterium enrichment is a mole percent and is obtainedby dividing the number of compounds with deuterium enrichment at thesite of enrichment with the number of compounds having hydrogen ordeuterium at the site of enrichment.

Definitions

As used herein, the term “pharmaceutically acceptable salt” refers topharmaceutical salts that are, within the scope of sound medicaljudgment, suitable for use in contact with the tissues of humans andlower animals without undue toxicity, irritation, and allergic response,and are commensurate with a reasonable benefit/risk ratio.Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al. describes pharmacologically acceptable saltsin J. Pharm. Sci. (1977) 66:1-19. Compounds of the present teachingswith basic groups can form pharmaceutically acceptable salts withpharmaceutically acceptable acid(s). Suitable pharmaceuticallyacceptable acid addition salts of the compounds described herein includesalts of inorganic acids (such as hydrochloric acid, hydrobromic,phosphoric, nitric, and sulfuric acids) and of organic acids (such asacetic acid, benzenesulfonic, benzoic, methanesulfonic, andp-toluenesulfonic acids). Compounds of the present teachings with acidicgroups can form pharmaceutically acceptable salts with pharmaceuticallyacceptable base(s). Suitable pharmaceutically acceptable basic saltsinclude ammonium salts, alkali metal salts (such as sodium and potassiumsalts) and alkaline earth metal salts (such as magnesium and calciumsalts).

The term “alkyl” used alone or as part of a larger moiety, such as“alkoxy”, “hydroxyalkyl” and the like, means a saturated aliphaticstraight-chain or branched monovalent hydrocarbon radical. Unlessotherwise specified, an alkyl group typically has 1 to 6 carbon atoms(C₁₋₆ alkyl), alternatively, 1 to 3 carbon atoms (C₁₋₃ alkyl). “C₁₋₆alkyl” is means a radical having 1 to 6 carbon atoms in a linear orbranched arrangement, such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert-butyl, and the like.

“Alkoxy” means an alkyl radical attached through an oxygen linking atom,represented by —O-alkyl, wherein alkyl is as defined above. For example,“C₁₋₆ alkoxy” includes methoxy, ethoxy, propoxy, butoxy, pentoxy,isopentoxy, isopropoxy, and hexoxy.

The term “halogen” or “halo” means fluorine or fluoro (F), chlorine orchloro (Cl), bromine or bromo (Br), or iodine or iodo (I).

“Cycloalkyl” means a saturated aliphatic cyclic hydrocarbon ringradical. Unless otherwise specified, a cycloalkyl has 3 to 8 ring carbonatoms (C₃₋₈ cycloalkyl) (i.e., 3, 4, 5, 6, 7, or 8), alternatively, 3 to6 ring carbon atoms (C₃₋₆ cycloalkyl) (i.e., 3, 4, 5, or 6),alternatively, 3 to 5 carbon atoms (C₃₋₅ cycloalkyl) (i.e., 3, 4, or 5).“C₃₋₆ Cycloalkyl” means a radical having from 3 to 6 carbon atomsarranged in a monocyclic ring. A C₃₋₆ cycloalkyl includes cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl. A C₃₋₅ cycloalkyl includescyclopropyl, cyclobutyl, and cyclopentyl.

The term “heterocycle” refers to a monocyclic non-aromatic ring radicalcontaining unless otherwise specified, 3 to 8 ring atoms (i.e., “3, 4,5, 6, 7, or 8 membered”) selected from carbon atom and 1 or 2heteroatoms. Each heteroatom is independently selected from nitrogen,quaternary nitrogen, oxidized nitrogen (e.g., NO); oxygen; and sulfur,including sulfoxide and sulfone. Representative heterocycles includemorpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl,piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, andthe like.

The term “substituted”, whether preceded by the term “optionally” ornot, refers to the replacement of a hydrogen substituent in a givenstructure with a non-hydrogen substituent. Thus, for example, asubstituted alkyl is an alkyl wherein at least one non-hydrogensubstituent is in the place of a hydrogen substituent on the alkylgroup. To illustrate, monofluoroalkyl is an alkyl substituted with afluoro substituent, and difluoroalkyl is an alkyl substituted with twofluoro substituents. It should be recognized that if there is more thanone substitution on a substituent, each non-hydrogen substituent can beidentical or different (unless otherwise stated).

If a group is described as being “optionally substituted”, the group canbe either (1) not substituted or (2) substituted.

If a group is described as being optionally substituted with up to aparticular number of non-hydrogen substituents, that group can be either(1) not substituted; or (2) substituted by up to that particular numberof non-hydrogen substituents or by up to the maximum number ofsubstitutable positions on the substituent, whichever is less. Thus, forexample, if a group is described as a cycloalkyl optionally substitutedwith up to 3 non-hydrogen substituents, then any cycloalkyl with lessthan 3 substitutable positions would be optionally substituted by up toonly as many non-hydrogen substituents as the cycloalkyl hassubstitutable positions.

Compounds having one or more chiral centers can exist in variousstereoisomeric forms, i.e., each chiral center can have an R or Sconfiguration or can be a mixture of both. Stereoisomers are compoundsthat differ only in their spatial arrangement. Stereoisomers include alldiastereomeric and enantiomeric forms of a compound. Enantiomers arestereoisomers that are mirror images of each other. Diastereomers arestereoisomers having two or more chiral centers that are not identicaland are not mirror images of each other.

When the stereochemical configuration at a chiral center in a compoundhaving one or more chiral centers is depicted by its chemical name(e.g., where the configuration is indicated in the chemical name by “R”or “S”) or structure (e.g., the configuration is indicated by “wedge”bonds), the enrichment of the indicated configuration relative to theopposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or99.9% (except when the designation “rac” or “racemate accompanies thestructure or name, as explained in the following two paragraphs).“Enrichment of the indicated configuration relative to the oppositeconfiguration” is a mole percent and is determined by dividing thenumber of compounds with the indicated stereochemical configuration atthe chiral center(s) by the total number of all of the compounds withthe same or opposite stereochemical configuration in a mixture.

When the stereochemical configuration at a chiral center in a compoundis depicted by chemical name (e.g., where the configuration is indicatedin the name by “R” or “S”) or structure (e.g., the configuration isindicated by “wedge” bonds) and the designation “rac” or “racemate”accompanies the structure or is designated in the chemical name, aracemic mixture is intended.

When two or more stereoisomers are depicted by their chemical names orstructures, and the names or structures are connected by an “or”, one orthe other of the two or more stereoisomers is intended, but not both.

When a disclosed compound having a chiral center is depicted by astructure without showing a configuration at that chiral center, thestructure is meant to encompass the compound with the S configuration atthat chiral center, the compound with the R configuration at that chiralcenter, or the compound with a mixture of the R and S configuration atthat chiral center. When a disclosed compound having a chiral center isdepicted by its chemical name without indicating a configuration at thatchiral center with “S” or “R”, the name is meant to encompass thecompound with the S configuration at that chiral center, the compoundwith the R configuration at that chiral center or the compound with amixture of the R and S configuration at that chiral center.

A racemic mixture means a mixture of 50% of one enantiomer and 50% ofits corresponding enantiomer. The present teachings encompass allenantiomerically-pure, enantiomerically-enriched, diastereomericallypure, diastereomerically enriched, and racemic mixtures, anddiastereomeric mixtures of the compounds described herein.

Enantiomeric and diastereomeric mixtures can be resolved into theircomponent enantiomers or stereoisomers by well known methods, such aschiral-phase gas chromatography, chiral-phase high performance liquidchromatography, crystallizing the compound as a chiral salt complex, orcrystallizing the compound in a chiral solvent. Enantiomers anddiastereomers can also be obtained from diastereomerically- orenantiomerically-pure intermediates, reagents, and catalysts by wellknown asymmetric synthetic methods.

“Peak 1” or “first eluting isomer” in the Experimental section refers toan intended reaction product compound obtained from a chromatographyseparation/purification that elutes earlier than a second intendedreaction product compound from the same preceding reaction. The secondintended product compound is referred to as “peak 2” or “second elutingisomer”.

When a compound is designated by a name or structure that indicates asingle enantiomer, unless indicated otherwise, the compound is at least60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as“enantiomerically pure”). Optical purity is the weight in the mixture ofthe named or depicted enantiomer divided by the total weight in themixture of both enantiomers.

When the stereochemistry of a disclosed compound is named or depicted bystructure, and the named or depicted structure encompasses more than onestereoisomer (e.g., as in a diastereomeric pair), it is to be understoodthat, unless otherwise indicated, one of the encompassed stereoisomersor any mixture of the encompassed stereoisomers are included. It is tobe further understood that the stereoisomeric purity of the named ordepicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% byweight. The stereoisomeric purity in this case is determined by dividingthe total weight in the mixture of the stereoisomers encompassed by thename or structure by the total weight in the mixture of all of thestereoisomers.

Use

Compounds of the disclosure are MAP4K1 inhibitors. The use of the word“inhibitor” means that a compound or a pharmaceutically acceptable saltthereof inhibits activity of MAP4K1. By “inhibit” herein is meant todecrease the activity of the target enzyme as compared to the activityof that enzyme in the absence of the inhibitor. In some alternatives,the term “inhibit” means a decrease in MAP4K1 activity of at least 5%,at least 10%, at least 20%, at least 50%, at least 60%, at least 79%, atleast 80%, at least 90% or at least 95%. In other alternatives, inhibitmeans a decrease in MAP4K1 activity of 5% to 25%, 25% to 50%, 50 to 70%,75 to 100%. In some embodiments, inhibit means a decrease in MAP4K1activity about 95% to 100%, e.g., a decrease in activity of 95%, 96%,97%, 98%, 99%, or 100%. Such decreases can be measured using a varietyof techniques that would be recognizable by one of skill in the art,including in vitro kinase assays.

Compounds of the disclosure are selective MAP4K1 inhibitors. As usedherein, a “selective MAP4K1 inhibitor” refers to a compound or apharmaceutically acceptable salt thereof that has the ability toselectively inhibit MAP4K1 kinase over other targets. More specifically,a selective MAP4K1 inhibitor has the ability to selectively inhibitMAP4K1 over another kinase. A selective MAP4K1 inhibitor has the abilityto selectively reduce target signaling activity relative to off-targetsignaling activity, via direct or indirect interaction with the target.The ability to selectively target MAP4K1 with a compound orpharmaceutically acceptable salt thereof provides advantages in terms ofimproved potency, less off-target activity and an increased probabilityof clinical success in comparison with a non-selective compound or salt.A MAP4K1 inhibitor that selectively inhibits MAP4K1 may have an activitythat is at least 2-fold relative to another kinase (e.g., at least10-fold; at least 15-fold; at least 20-fold; at least 30-fold; at least40-fold selectivity; at least 50-fold; at least 60-fold; at least70-fold; at least 80-fold; at least 90-fold; at least 100-fold; at least125-fold; at least 150-fold; at least 175-fold; or at least 200-fold. Insome alternatives, a selective MAP4K1 inhibitor exhibits at least15-fold selectivity over another kinase, e.g., LCK and MAP4K familymembers (MAP4K4 (HGK) and MAP4K3 (GLK)). In some alternatives, theselective MAP4K1 inhibitors are selective over EGFR and L858R/T790MEGFR. In some alternatives, the selective MAP4K1 inhibitors of thedisclosure are selective over BTK. In some alternatives, the selectiveMAP4K1 inhibitors of the disclosure are selective over JNK.

The disclosure provides methods of modulating (e.g., inhibiting) MAP4K1activity in a patient in need thereof, said method comprisingadministering to the patient a compound provided herein, or apharmaceutically acceptable salt thereof. In certain embodiments, thecompounds of the disclosure, or pharmaceutically acceptable saltsthereof, are useful for therapeutic administration to enhance, stimulateand/or increase immunity in patients in need thereof, e.g., in cancerpatients or patients with viral infection. In some instances, thecompounds of the disclosure, or pharmaceutically acceptable saltsthereof reduce, inhibit, or otherwise diminish pSLP76. In someinstances, the compounds of the disclosure, or pharmaceuticallyacceptable salts thereof, are useful for therapeutic administration toenhancing at least one of activation, priming, migration, proliferation,survival and cytolytic activity of T cells relative to prior toadministration. In certain aspects, T cell activation is characterizedby enhanced levels of IL-2, IFN-gamma, or granzyme B production by Tcells relative to prior to administration of the compound orpharmaceutically acceptable salt thereof. In some instances, thecompounds of the disclosure, or pharmaceutically acceptable saltsthereof, are useful for therapeutic administration to induce a change incell cycle or cell viability. In some instances, the compounds of thedisclosure, or pharmaceutically acceptable salts thereof, are useful forimproving function of T effector cells. In some instances, the compoundsof the disclosure, or pharmaceutically acceptable salts thereof, areuseful for inhibiting the suppressive effects of T regulatory cells orimproving the T cell response to immune suppressive factors includingadenosine and PGE2. In some instances, the compounds of the disclosure,or pharmaceutically acceptable salts thereof, are useful for increasingthe frequency of CD8+ tumor infiltrating lymphocytes (TILS). In someinstances, the compounds of the disclosure, or pharmaceuticallyacceptable salts thereof are useful for enhancing CD8+/Treg ratios. Insome instances, the compounds of the disclosure, or pharmaceuticallyacceptable salts thereof, are useful for enhancing cytokines. In someinstances, the compounds of the disclosure, or pharmaceuticallyacceptable salts thereof, are useful for enhanacing cytokines with noimpact on IL-6. In some instances, the compounds of the disclosure, orpharmaceutically acceptable salts there, indirectly inhibit the growthof cancer cells. In some instances, the compounds of the disclosure, orpharmaceutically acceptable salts thereof, are useful for priming of theimmune response (i.e., vaccines) to tumors or viruses for boosting orgenerating anti-viral/anti-tumor immunity. In one instance, thecompounds of the disclosure, or pharmaceutically acceptable saltsthereof, are useful for enhacing or boosting response to a vaccine (suchas a cancer vaccine or a personalized cancer vaccine (PCV)) or a CAR-Tcell therapy.

Methods of treating a MAP4K1-dependent disease or disorder can includeadministering to a patient in need thereof a therapeutically effectiveamount of a compound provided herein, or a pharmaceutically acceptablesalt thereof. For example, the MAP4K1-dependent disease or disorder is acancer. The term “cancer” encompasses all forms of cancer including, butnot limited to, all forms of carcinoma, melanomas, blastomas, sarcomas,lymphomas, leukemias. In some embodiments, cancer includes metastaticforms. Additionally, the disclosure includes refractory or recurrentmalignancies whose growth may be inhibited using the compounds of thedisclosure or pharmaceutically acceptable salts thereof. For the usesdescribed herein, any of the compounds of the disclosure, orpharmaceutically acceptable salts thereof, may be used alone or incombination with other therapeutic agents.

In some embodiments, the treatment results in a sustained response inthe subject after cessation of the treatment. “Sustained response”refers to the sustained effect on reducing tumor growth after cessationof a treatment. For example, the tumor size may remain the same orsmaller as compared to the size at the beginning of the administrationphase. In some embodiments, the sustained response has a duration atleast the same as the treatment duration, at least 1.5×, 2.0×, 2.5×, or3.0× length of the treatment duration.

The treatment methods disclosed herein may result in a partial orcomplete response. As used herein, “complete response” or “CR” refers todisappearance of all target lesions; “partial response” or “PR” refersto at least a 30% decrease in the sum of the longest diameters (SLD) oftarget lesions, taking as reference the baseline SLD; and“stabledisease” or “SD” refers to neither sufficient shrinkage of targetlesions to qualify for PR, nor sufficient increase to qualify for PD,taking as reference the smallest SLD since the treatment started. Asused herein, “overall response rate” (ORR) refers to the sum of completeresponse (CR) rate and partial response (PR) rate.

The treatment methods disclosed herein can lead to an increase inprogression free survival and overall survival of the subjectadministered the selective MAP4K1 inhibitor. As used herein,“progression free survival” (PFS) refers to the length of time duringand after treatment during which the disease being treated (e.g.,cancer) does not get worse. Progression-free survival may include theamount of time patients have experienced a complete response or apartial response, as well as the amount of time patients haveexperienced stable disease.

As used herein, “overall survival” (OS) refers to the percentage ofsubjects in a group who are likely to be alive after a particularduration of time.

In some embodiments, cancers treatable with compounds of the disclosureor pharmaceutically acceptable salts thereof, include colon cancer,pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovariancancer, cervical cancer, renal cancer, bladder cancer, stomach cancer,liver cancer, gastric cancer, cancer of the head and neck, lymphoma,leukemia, urothelial carcinoma, merkel cell carcinoma, gastroesophagealjunction carcinoma, esophageal squamous cell carcinoma, skin squamouscell carcinoma and melanoma.

In some embodiments, cancers treatable with compounds of the disclosureor pharmaceutically acceptable salts thereof, include colon cancer,pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovariancancer, cervical cancer, renal cancer, bladder cancer, stomach cancer,liver cancer, cancer of the head and neck, lymphoma, leukemia, andmelanoma.

In some embodiments, cancers that are treatable using the compounds ofthe disclosure or pharmaceutically acceptable salts thereof, include,but are not limited to, solid tumors, including prostate cancer, coloncancer, esophageal cancer, endometrial cancer, ovarian cancer, uterinecancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer,breast cancer, lung cancer, head and neck cancer, thyroid cancer, braincancer, and bladder cancer and hematological cancer, including lymphoma,leukemia (chronic and acute forms) such as ALL, AML, CLL, CML, DLBCL,mantle cell lymphoma, Non-Hodgkin's lymphoma (NHL), including relapsedor refractory NHL and recurrent follicular, Hodgkin's lymphoma andmultiple myeloma, and myeloproliferative diseases.

In some embodiments, diseases and indications that are treatable usingthe compounds of the disclosure or pharmaceutically acceptable saltsthereof, include, but are not limited to hematological cancer, sarcomas,respiratory cancer, gastrointestinal cancer, genitourinary tract cancer,liver cancer, bone cancer, nervous system cancer, gynecological cancer,and skin cancer.

Exemplary hematological cancer includes, for example, lymphomas andleukemias such as ALL, AML, acute promyelocyte leukemia (APL), CLL, CML,DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (NHL), includingPrimary mediastinal B-cell lymphoma (PMBCL), relapsed or refractory NHL,recurrent follicular, and primary CNS lymphoma, Hodgkin's lymphoma,myeloproliferative diseases, including, primary myelofibrosis (PMF),polycythemia vera (PV), essential thrombocytosis (ET), myelodysplasiasyndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiplemyeloma, cutaneous T-cell lymphoma, Waldenstrom's Macroglubulinemia,hairy cell lymphoma, chronic myelogenic lymphoma, and Burkitt'slymphoma.

Exemplary sarcoma includes, for example, chondrosarcoma, Ewing'ssarcoma, Kaposi's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma,fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdosarcoma, fibroma,lipoma, harmatoma, sarcoma of the soft tissue, and teratoma.

Exemplary respiratory tract cancer includes, for example, lung cancersuch as non-small cell lung cancer (NSCLC), small cell lung cancer,epidermoid cancer, bronchogenic carcinoma, including squamous cell,undifferentiated small cell, undifferentiated large cell,adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma,chondromatous hamartoma, mesothelioma, and pleuropulmonary blastoma.

Exemplary gastrointestinal cancer includes, for example, cancers of theesophagus, including squamous cell carcinoma, adenocarcinoma,leiomyosarcoma, and lymphoma; stomach, including carcinoma, lymphoma,and leiomyosarcoma; pancreas, including ductal adenocarcinoma,insulinoma, glucagonoma, gastrinoma, carcinoid tumors, and vipoma; smallinstestine, including adenocarcinoma, lymphoma, carcinoid tumors,Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, andfibroma; large intestine, including adenocarcinoma, tubular adenoma,villous adenoma, hamartoma, and leiomyoma; colon; and gall bladder,including adenocarcinoma; and intestinal type and diffuse type gastricadenocarcinoma, rectum carcinoma, familiar adenomatous polyposiscarcinoma and hereditary non-polyposis colorectal cancer.

Exemplary genitourinary tract cancer includes, for example, cancers ofthe kidney, including adenocarcinoma, Wilm's tumor [nephroblastoma],renal cell carcinoma, urothelial carcinoma, juxtaglomerular cell tumor(reninoma), angiomyolipoma, renal oncocytoma, Bellinio duct carcinoma,clear-cell sarcoma of the kidney, and mesoblastic nephroma; adrenalgland; renal pelvis; bladder, including transitional cell carcinoma,squamous cell carcinoma, adenocarcinoma, sarcoma, and small cellcarcinoma; urethra, including squamous cell carcinoma, transitional cellcarcinoma, and adenocarcinoma; prostate, including adenocarcinoma,sarcoma, and carcinoma; testis, including seminoma, teratoma, embryonalcarcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cellcarcinoma, fibroma, fibroadenoma, adenomatoid tumors, and lipoma; penis;and pancreas.

Exemplary liver cancer includes, for example, hepatoma, includinghepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, biliary tract cancer, andhemangioma.

Exemplary bone cancer includes, for example, osteogenic sarcoma,fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing'ssarcoma, malignant lymphoma, including reticulum cell sarcoma, multiplemyeloma, malignant giant cell tumor chordoma, osteochronfroma, includingosteocartilaginous exostoses, benign chondroma, chondroblastoma,chondromyxofibroma, osteoid osteoma, and giant cell tumors

Exemplary nervous system cancer includes, for example, cancer of theskull, including osteoma, hemangioma, granuloma, xanthoma, and osteitisdeformans; meninges including, meningioma, meningiosarcoma, andgliomatosis; brain, including astrocytoma, meduoblastoma, glioma,ependymoma, germinoma (pinealoma), neuroectodermal tumor, glioblastoma,glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma,congenital tumors, brain stem and hypopthamic glioma; and spinal cord,including neurofibroma, meningioma, glioma, and sarcoma; as well asneuroblastoma and Lhermitte-Duclos disease.

Exemplary gynecological cancer includes, for example, cancer of theuterus, including endometrial carcinoma; cervix, including cervicalcarcinoma, pre-tumor cervical dysplasia, squamouse cell carcinoma,adenocarcinoma, adenosquamous carcinoma, small cell carcinoma,neuroendocrine tumor, glassy cell carcinoma and villoglandularadenocarcinoma; ovaries, including ovarian carcinoma (serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma,endometroid tumor), granulosa-thecal cell tumors, Sertoli-Leydig celltumors, dysgerminoma, malignant teratoma, and arrhenoblastoma; vulva(squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma,fibrosarcoma, and melanoma; vagina, including clear cell carcinoma,squamous cell carcinoma, and botryoid sarcoma (embryonalrhabdomyosarcoma); labia; and fallopian tubes.

Exemplary skin cancer includes, for example, melanoma, sebaceous glandcarcinoma, basal cell carcinoma, squamous cell carcinoma, Kaposi'ssarcoma, Merkel cell skin cancer, moles dysplastic nevi, lipoma,angioma, dermatofibroma, and keloids.

Examples of breast cancer include, for example, ER+/HER2− breast cancer,triple-negative breast cancer (TNBC), invasive ductal carcinoma,invasive lobular carcinoma, ductal carcinoma in situ, and lobularcarcinoma in situ.

Exemplary head and neck cancer includes, for example, glioblastoma,melanoma, rhabdosarcoma, lymphosarcoma, osteosarcoma, squamous cellcarcinomas, adenocarcinomas, oral cancer, throat cancer, includingoropharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, nasal andparanasal cancer, salivary gland cancer, mouth cancer, eye cancer,acoustic neuroma, pituitary adenoma, hypopharngx, and thyroid (medullaryand papillary) and parathyroid cancer.

Other cancers include, for example, sweat gland cancer, spinal axistumor, chest cancer, sickle cell anemia, and environmentally inducedcancers including those induced by asbestos.

In some instances, the MAP4K1-dependent disease or disorder is a viralinfection, such as infection caused by hepatitis B virus (HBV),hepatitis C virus (HCV), human papilloma virus (HPV), cytomegalovirus(CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), varicellazoster virus, coxsackie virus, and human immunodeficiency virus (HIV).

Combination Therapies

Compounds of the disclosure or pharmaceutically acceptable saltsthereof, can be administered as the sole pharmaceutical agent or incombination with one or more other anti-cancer agents for the treatmentof cancer, where the combination causes no unacceptable adverse effects.In some embodiments, the other anti-cancer agents are immune-oncologyagent, anticancer agents that are enzyme/protein/receptor inhibitors,radiation or chemotherapy.

Compounds of the disclosure or pharmaceutically acceptable saltsthereof, can be co-formulated with an immuno-oncology agent.Immuno-oncology agents include, for example, a small molecule drug,antibody, or other biologic or small molecule. Examples of biologicimmuno-oncology agents include, but are not limited to, cancer vaccines,antibodies, and cytokines. In one aspect, the antibody is a monoclonalantibody. In another aspect, the monoclonal antibody is humanized orhuman. In another aspect, the antibody is a bispecific antibody.

In one aspect, the immuno-oncology agent is (i) an agonist of astimulatory (including a co-stimulatory) receptor or (ii) an antagonistof an inhibitory (including a co-inhibitory) signal on T cells, both ofwhich result in amplifying antigen-specific T cell responses (oftenreferred to as immune checkpoint regulators).

Certain of the stimulatory and inhibitory molecules are members of theimmunoglobulin super family (IgSF). One important family ofmembrane-bound ligands that bind to co-stimulatory or co-inhibitoryreceptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1),B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6.Another family of membrane bound ligands that bind to co-stimulatory orco-inhibitory receptors is the TNF family of molecules that bind tocognate TNF receptor family members, which includes CD40 and CD40L,OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB),TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK,RANKL, TWEAKR/Fnl4, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTfiR,LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1,Lymphotoxin α/TNPβ, TNFR2, TNF a, LTR, Lymphotoxin a 1β2, FAS, FASL,RELT, DR6, TROY, NGFR.

In one aspect, T cell responses can be stimulated by a combination of acompound of the disclosure or a pharmaceutically acceptable saltthereof, and one or more of (i) an antagonist of a protein that inhibitsT cell activation (e.g., immune checkpoint inhibitors) such as CTLA-4,PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69,Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1,TIM-1, and TIM-4, and (ii) an agonist of a protein that stimulates Tcell activation such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS,ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H.

Other agents that can be combined with compounds of the disclosure orpharmaceutically acceptable salts thereof, for the treatment of cancerinclude antagonists of inhibitory receptors on NK cells or agonists ofactivating receptors on NK cells. For example, compounds of thedisclosure can be combined with antagonists of KIR, such as lirilumab.

Yet other agents for combination therapies include agents that inhibitor deplete macrophages or monocytes, including but not limited to CSF-1Rantagonists such as CSF-1R antagonist antibodies including RG7155 orFPA-008.

In another aspect, compounds of the disclosure or pharmaceuticallyacceptable salts thereof, can be used with one or more of agonisticagents that ligate positive costimulatory receptors, blocking agentsthat attenuate signaling through inhibitory receptors, antagonists, andone or more agents that increase systemically the frequency ofanti-tumor T cells, agents that overcome distinct immune suppressivepathways within the tumor microenvironment (e.g., block inhibitoryreceptor engagement (e.g., PD-L1/PD-1 interactions), deplete or inhibitTregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab)or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes suchas IDO, or reverse/prevent T cell anergy or exhaustion) and agents thattrigger innate immune activation and/or inflammation at tumor sites.

In some embodiments, the immuno-oncology agent is a CTLA-4 antagonist,such as an antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodiesinclude, for example, YERVOY (ipilimumab) or tremelimumab. In anotheraspect, the immuno-oncology agent is a PD-1 antagonist, such as anantagonistic PD-1 antibody. Suitable PD-1 antibodies include, forexample, OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680(AMP-514; WO2012/145493). The immuno-oncology agent may also includepidilizumab (CT-011), though its specificity for PD-1 binding has beenquestioned. Another approach to target the PD-1 receptor is therecombinant protein composed of the extracellular domain of PD-L2(B7-DC) fused to the Fc portion of IgG1, called AMP-224

In another aspect, the immuno-oncology agent is a PD-L1 antagonist, suchas an antagonistic PD-L1 antibody. Suitable PD-L1 antibodies include,for example, TECENTRIQ (atezolizumab) (RG7446; WO2010/077634),durvalumab (MEDI4736), BMS-936559 (WO2007/005874), and MSB0010718C(WO2013/79174).

In another aspect, the immuno-oncology agent is a LAG-3 antagonist, suchas an antagonistic LAG-3 antibody. Suitable LAG3 antibodies include, forexample, BMS-986016 (WO10/19570, WO14/08218), or IMP-731 or IMP-321(WO08/132601, WO09/44273).

In another aspect, the immuno-oncology agent is a CD137 (4-1BB) agonist,such as an agonistic CD137 antibody. Suitable CD137 antibodies include,for example, urelumab and PF-05082566 (WO12/32433).

In another aspect, the immuno-oncology agent is a GITR agonist, such asan agonistic GITR antibody. Suitable GITR antibodies include, forexample, BMS-986153, BMS-986156, TRX-518 (WO06/105021, WO09/009116) andMK-4166 (WOl 1/028683).

In another aspect, the immuno-oncology agent is an IDO antagonist.Suitable IDO antagonists include, for example, INCB-024360(WO2006/122150, WO07/75598, WO08/36653, WO08/36642), indoximod, orNLG-919 (WO09/73620, WO09/1156652, WOl11/56652, WO12/142237).

In another aspect, the immuno-oncology agent is an OX40 agonist, such asan agonistic OX40 antibody. Suitable OX40 antibodies include, forexample, MEDI-6383 or MEDI-6469. In another aspect, the immuno-oncologyagent is an OX40L antagonist, such as an antagonistic OX40 antibody.Suitable OX40L antagonists include, for example, RG-7888 (WO06/029879).

In another aspect, the immuno-oncology agent is a CD40 agonist, such asan agonistic CD40 antibody. In yet another embodiment, theimmuno-oncology agent is a CD40 antagonist, such as an antagonistic CD40antibody. Suitable CD40 antibodies include, for example, lucatumumab ordacetuzumab.

In another aspect, the immuno-oncology agent is a CD27 agonist, such asan agonistic CD27 antibody. Suitable CD27 antibodies include, forexample, varlilumab.

In another aspect, the immuno-oncology agent is MGA271 (to B7H3) (WOl1/109400).

The compounds of the disclosure or pharmaceutically acceptable saltsthereof, can be used in combination with anticancer agents that areenzyme/protein/receptor inhibitors, exhibiting different preferences inthe targets which they modulate the activities of, to treat suchconditions. Targeting more than one signaling pathway (or more than onebiological molecule involved in a given signaling pathway) may reducethe likelihood of drug-resistance arising in a cell population, and/orreduce the toxicity of treatment.

The compounds of the disclosure or pharmaceutically acceptable saltsthereof, can be used in combination with one or more otherenzyme/protein/receptor inhibitors for the treatment of cancer. Forexample, the compounds of the disclosure or pharmaceutically acceptablesalts thereof, can be combined with one or more inhibitors of thefollowing kinases for the treatment of cancer: Akt1, Akt2, Akt3,TGF-βPv, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK,MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFotR,PDGFpR, CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2,FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4,EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak,SYK, FRK, JAK, ABL, ALK, and B-Raf.

In some embodiments, the compounds of the disclosure or pharmaceuticallyacceptable salts thereof, can be combined with one or more of thefollowing inhibitors for the treatment of cancer. Non-limiting examplesof inhibitors that can be combined with the compounds of the presentdisclosure for treatment of cancers include an FGFR inhibitor (FGFR1,FGFR2, FGFR3 or FGFR4, e.g., fisogatinib, AZD4547, BAY 1187982, ARQ087,BGJ398, BIBF1120, TKI258, lucitanib, dovitinib, TAS-120, J J-42756493,Debiol347, INCB54828, INCB62079, and INCB63904), a JAK inhibitor (JAK1and/or JAK2, e.g., ruxolitinib, baricitinib, or itacitinib (INCB39110)),an IDO inhibitor (e.g., epacadostat and NLG919), an LSD1 inhibitor(e.g., GSK2979552, INCB59872 and INCB60003), a TDO inhibitor, aPI3K-delta inhibitor (e.g., INCB50797 and INCB50465), a PI3K-gammainhibitor such as a PI3K-gamma selective inhibitor (eganelisib) or adual PI3K-delta/gamma selective inhibitor (duvelisib), a CSF1R inhibitor(e.g., PLX3397 and LY3022855), a TAM receptor tyrosine kinases (Tyro-3,Axl, and Mer), an angiogenesis inhibitor (Such as Avastin(bevacizumab)), an interleukin receptor inhibitor, bromo and extraterminal family members inhibitors (for example, bromodomain inhibitorsor BET inhibitors such as OTX015, CPI-0610, INCB54329, and INCB57643),and an adenosine receptor antagonist or combinations thereof. Inhibitorsof HDAC such as panobinostat and vorinostat can be combined with thecompounds of the disclosure. Inhibitors of c-Met such as onartumzumab,tivantnib, and capmatinib (INC-280) be combined with the compounds ofthe disclosure or pharmaceutically acceptable salts thereof. Inhibitorsof BTK such as ibrutinib can be combined with the compounds of thedisclosure or pharmaceutically acceptable salts thereof. Inhibitors ofmTOR such as rapamycin, sirolimus, temsirolimus, and everolimus can becombined with the compounds of the disclosure or pharmaceuticallyacceptable salts thereof. Inhibitors of Raf, such as vemurafenib anddabrafenib can be combined with the compounds of the disclosure orpharmaceutically acceptable salts thereof. Inhibitors of MEK such astrametinib, selumetinib and GDC-0973 can be combined with the compoundsof the disclosure or pharmaceutically acceptable salts thereof.Inhibitors of KIT, including avapritinib, imatinib, sunitinib,regorafenib, ripritinib (DCC2618), PLX9486, PLX3397, crenolanib,CDX-0158, CDX-0159. Inhibitors of RET including pralsetinib,selperctinib, alectinib, levatinib, cabozantinib, BOS172738 (DS-5010),SL-1001, TPX-0046, sitravatinib (MGCD516), and RXDX-105. Inhibitors ofHsp90 (e.g., tanespimycin), cyclin dependent kinases (e.g.,palbociclib), PARP (e.g., olaparib) and Pim kinases (LGH447, INCB053914,and SGI-1776) can also be combined with compounds of the disclosure orpharmaceutically acceptable salts thereof.

Compounds of the disclosure or pharmaceutically acceptable saltsthereof, can be used in combination with one or more agents for thetreatment of cancer. In some embodiments, the agent is an alkylatingagent, a proteasome inhibitor, a corticosteroid, or an immunomodulatoryagent. Examples of an alkylating agent include bendamustine, nitrogenmustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas andtriazenes, uracil mustard, chlormethine, cyclophosphamide (CYTOXAN),ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine,triethylenethiophosphoramine, busulfan, carmustine, lomustine,streptozocin, dacarbazine, and temozolomide. In some embodiments, theproteasome inhibitor is carfilzomib. In some embodiments, thecorticosteroid is dexamethasone (DEX).

The compounds of the disclosure or pharmaceutically acceptable saltsthereof, can be administered in combination with one or more anti-cancerdrugs, such as a chemotherapeutics. Example chemotherapeutics includeany of: abarelix, abiraterone, afatinib, aflibercept, aldesleukin,alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole,arsenic trioxide, asparaginase, axitinib, azacitidine, bevacizumab,bexarotene, baricitinib, bicalutamide, bleomycin, bortezombi,bortezomib, brivanib, buparlisib, busulfan intravenous, busulfan oral,calusterone, capecitabine, carmustine, cediranib, cetuximab,chlorambucil, cladribine, clofarabine, crizotinib, cyclophosphamide,cytarabine, dacarbazine, dacomitinib, dactinomycin, dalteparin sodium,dasatinib, dactinomycin, daunorubicin, decitabine, degarelix,denileukin, denileukin diftitox, deoxycoformycin, dexrazoxane,docetaxel, doxorubicin, droloxifene, dromostanolone propionate,eculizumab, enzalutamide, epidophyllotoxin, epirubicin, erlotinib,estramustine, etoposide phosphate, etoposide, exemestane, fentanylcitrate, filgrastim, floxuridine, fludarabine, fluorouracil, flutamide,fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelinacetate, histrelin acetate, ibritumomab tiuxetan, idarubicin,idelalisib, ifosfamide, imatinib mesylate, interferon alfa 2a,irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin,leuprolide acetate, levamisole, lomustine, meclorethamine, megestrolacetate, melphalan, mercaptopurine, methotrexate, methoxsalen,mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolonephenpropionate, navelbene, necitumumab, nelarabine, neratinib,nilotinib, nilutamide, nofetumomab, oserelin, paclitaxel, pamidronate,panitumumab, pazopanib, pegaspargase, pegfilgrastim, pemetrexeddisodium, pentostatin, pilaralisib, pipobroman, plicamycin, cisplatin,carboplatin, oxaliplatin, ponatinib, prednisone, procarbazine,quinacrine, rasburicase, regorafenib, reloxafine, rituximab,ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate,tamoxifen, tegafur, temozolomide, teniposide, testolactone, thalidomide,thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab,tretinoin, triptorelin, uracil mustard, valrubicin, vandetanib,vinblastine, vincristine, vinorelbine, vorinostat, and zoledronate.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin).

Compounds of the disclosure or pharmaceutically acceptable saltsthereof, can be administered as the sole pharmaceutical agent or incombination with one or more anti-viral agents for the treatment ofchronic viral infections, where the combination causes no unacceptableadverse effects. Chronic viral infections include, but are not limitedto, diseases caused by: hepatitis C virus (HCV), human papilloma virus(HPV), cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barrvirus (EBV), varicella zoster virus, coxsackie virus, humanimmunodeficiency virus (HIV). Parasitic infections (e.g., malaria) mayalso be treated by the above methods wherein compounds known to treatthe parasitic conditions are optionally added in place of the antiviralagents.

Suitable antiviral agents contemplated for use in combination with thecompounds of the disclosure or pharmaceutically acceptable saltsthereof, can comprise nucleoside and nucleotide reverse transcriptaseinhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors(NNRTIs), protease inhibitors and other antiviral drugs.

Examples of suitable NRTIs include zidovudine (AZT); didanosine (ddl);zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir(1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194);BCH-I0652; emitricitabine [(−)-FTC]; beta-L-FD4 (also called beta-L-D4Cand named beta-L-2′,3′-dicleoxy-5-fluoro-cytidene); DAPD,((−)-beta-D-2,6-diamino-purine dioxolane); and Iodenosine (FddA).Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine(BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrirnidinedione);and (+)-calanolide A (NSC-675451) and B. Typical suitable proteaseinhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538);indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir(BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1549. Otherantiviral agents include hydroxyurea, ribavirin, IL-2, IL-12,pentafuside and Yissum Project No. 11607.

When more than one pharmaceutical agent is administered to a patient,they can be administered simultaneously, separately, sequentially, or incombination (e.g., for more than two agents). For examples, whenadministered together with an additional anti-cancer or antiviral agent,the disclosed compounds or pharmaceutically acceptable salts thereof,can be administered simultaneously in the same pharmaceuticalformulation or simultaneously in separate pharmaceutical formulations.Alternatively, when administered together with an additional anti-canceror antiviral agent, the disclosed compounds or pharmaceuticallyacceptable salts thereof, can be administered at separate times,depending the dosing requirements of the additional anti-cancer orantiviral agent.

Pharmaceutical compositions are disclosed that include one or morecompounds provided herein (such as the compound of Formulas I-IV,V(A)-V(C), VI(A)-VI(C), VII-IX, VII(A)-IX(A) and X) or pharmaceuticallyacceptable salts thereof, and typically at least one additionalsubstance, such as an excipient, a known therapeutic other than those ofthe disclosure, and combinations thereof. In some embodiments, thedisclosed compounds or pharmaceutically acceptable salts thereof, can beused in combination with other agents known to have beneficial activitytargeting diseases or disorders listed above. For example, disclosedcompounds or pharmaceutically acceptable salts thereof, can beadministered alone or in combination with one or more anti-cancer orantiviral agent, and the pharmaceutically acceptable salts of thesecompounds.

The terms “administer”, “administering”, “administration”, and the like,as used herein, refer to methods that may be used to enable delivery ofcompositions to the desired site of biological action. These methodsinclude, but are not limited to, intraarticular (in the joints),intravenous, intramuscular, intratumoral, intradermal, intraperitoneal,subcutaneous, orally, topically, intrathecally, inhalationally,transdermally, rectally, and the like. Administration techniques thatcan be employed with the agents and methods described herein are foundin e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics,current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (currentedition), Mack Publishing Co., Easton, Pa.

A “subject” is a mammal in need of medical treatment, preferably ahuman, but can also be an animal in need of veterinary treatment, e.g.,companion animals (e.g., dogs, cats, and the like), farm animals (e.g.,cows, sheep, pigs, horses, and the like) and laboratory animals (e.g.,rats, mice, guinea pigs, and the like).

The precise amount of compound or pharmaceutically acceptable saltthereof, administered to provide an “effective amount” to the subjectwill depend on the mode of administration, the type, and severity of thedisease or condition, and on the characteristics of the subject, such asgeneral health, age, sex, body weight, and tolerance to drugs. Theskilled artisan will be able to determine appropriate dosages dependingon these and other factors. When administered in combination with othertherapeutic agents, e.g., when administered in combination with ananti-cancer or antiviral agent, an “effective amount” of any additionaltherapeutic agent(s) will depend on the type of drug used. Suitabledosages are known for approved therapeutic agents and can be adjusted bythe skilled artisan according to the condition of the subject, the typeof condition(s) being treated and the amount of a compound of thedisclosure or pharmaceutically acceptable salt thereof, being used byfollowing, for example, dosages reported in the literature andrecommended in the Physician's Desk Reference (57th ed., 2003).

The term “effective amount” means an amount when administered to thesubject which results in beneficial or desired results, includingclinical results, e.g., inhibits, suppresses or reduces the symptoms ofthe condition being treated in the subject as compared to a control. Forexample, a therapeutically effective amount can be given in unit dosageform (e.g., 0.1 mg to about 50 g per day, alternatively from 1 mg toabout 5 grams per day; and in another alternatively from 10 mg to 1 gramper day).

The particular mode of administration and the dosage regimen will beselected by the attending clinician, taking into account the particularsof the case (e.g. the subject, the disease, the disease state involved,the particular treatment, and whether the treatment is prophylactic).Treatment can involve daily or multi-daily or less than daily (such asweekly or monthly etc.) doses over a period of a few days to months, oreven years.

The pharmaceutical composition of the disclosure is formulated to becompatible with its intended route of administration. In an embodiment,the composition is formulated in accordance with routine procedures as apharmaceutical composition adapted for intravenous, subcutaneous,intramuscular, oral, intranasal, or topical administration to humanbeings. In preferred embodiments, the pharmaceutical composition isformulated for intravenous administration.

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptablecarrier” refer to a substance that aids the formulation and/oradministration of an active agent to and/or absorption by a subject andcan be included in the compositions of the present disclosure withoutcausing a significant adverse toxicological effect on the subject.Non-limiting examples of pharmaceutically acceptable excipients includewater, NaCl, normal saline solutions, lactated Ringer's, normal sucrose,normal glucose, binders, fillers, disintegrants, lubricants, coatings,sweeteners, flavors, salt solutions (such as Ringer's solution),alcohols, oils, gelatins, carbohydrates such as lactose, amylose orstarch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine,and colors, and the like. Such preparations can be sterilized and, ifdesired, mixed with auxiliary agents such as lubricants, preservatives,stabilizers, wetting agents, emulsifiers, salts for influencing osmoticpressure, buffers, coloring, and/or aromatic substances and the likethat do not deleteriously react with or interfere with the activity ofthe compounds provided herein. One of ordinary skill in the art willrecognize that other pharmaceutical excipients are suitable for use withdisclosed compounds.

General Synthetic Methods and Intermediates

Compounds of the disclosure, including salts and N-oxides thereof, canbe prepared using organic synthesis techniques known to one of ordinaryskill in the art and/or by reference to the schemes shown below and thesynthetic examples. The below Schemes are synthetic protocols that aremeant to provide general guidance in connection with preparing thecompounds of the disclosure. One skilled in the art would understandthat the preparations shown in the Schemes can be modified or optimizedusing general knowledge of organic chemistry to prepare variouscompounds of the disclosure.

The reactions for preparing compounds of the disclosure can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the disclosure can involve the protectionand deprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in Wuts and Greene,Protective Groups in Organic Synthesis, 5th ed., John Wiley & Sons: NewJersey, (2014), which is incorporated herein by reference in itsentirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance (NMR) spectroscopy (e.g., ¹Hor ¹³C), infrared (IR) spectroscopy, spectrophotometry (e.g.,UV-visible), mass spectrometry (MS), or by chromatographic methods suchas high performance liquid chromatography (HPLC) or thin layerchromatography (TLC).

Scheme 1 shows a synthetic protocol for the preparation of compounds offormula via and vib.

In Scheme 1, the definition of R is R⁶ as described for the embodimentsof the disclosure.

The 8-Alkoxy-2,7-Napthyridine methylketone i (see scheme 3 forpreparation of i) can be reduced with sodium borohydride in methanol togive ii. The alcohol ii can be coupled to the aniline under Pd-catalyzedcoupling conditions to give iii. The benzylic alcohol iii can be treatedwith TMSN₃ and Indium bromide in dichloromethane to yield thecorresponding azide intermediate iv. The azide iv can be reduced undertypical hydrogenation conditions such as Pd and H₂ to give the amine v.Chiral SFC on the racemic amine v can yield the desired isomer via andvib (arbitrarily assigned) which are examples of MAP4K1 inhibitorsdescribed herein.

Scheme 2 shows a synthetic protocol for the preparation of compounds offormula iv.

In Scheme 2, the definition of R is R⁶ or R⁷ as described for theembodiments of the disclosure. The other variables in Scheme 2 are asdescribed for the embodiments of the disclosure.

8-alkoxy-substituted 2,7-Napthyridine benzylic alcohol intermediate i(see Scheme 3 for preparation of i) can be coupled with an aniline underPd-catalyzed coupling conditions to give ii. Compound ii can be treatedwith TMSN₃ and Indium bromide in dichloromethane to yield thecorresponding azide intermediate iii. The azide iii can be reduced undertypical hydrogenation conditions such as Pd and H₂ to give the amine ivwhich are examples of MAP4K1 inhibitors described herein.

Scheme 3 shows a synthetic protocol for the preparation of compounds offormula viii.

In Scheme 3, the definition of R is R⁶ or R⁷ as described for theembodiments of the disclosure and X is O or N. The other variables areas described for the embodiments of the disclosure.

Tri-halogen intermediate i (see Intermediate 31 in common intermediatesfor synthesis of intermediate i) can be treated with an alcohol or anamine to yield intermediate ii. Intermediate ii can be subjected toStille coupling with tributyl(1-ethoxyvinyl)stannane to yield iii. Underacidic conditions, iii can be converted to the methyl ketone iv.Subsequent addition of alkyl lithium or alkyl magnesium bromide canyield intermediate v. Compound v can be treated with TMSN₃ and Indiumbromide in dichloromethane to yield the corresponding azide intermediatevi. The azide vi can be coupled to aryl amines under Pd-catalyzedcoupling conditions to yield vii. Compound vii can be reduced undertypical hydrogenation conditions such as Pd and H₂ to give the amineviii which are examples of MAP4K1 inhibitors described herein. The finalamine viii can be separated using chromatography into isomers.

Scheme 4 shows a synthetic protocol for the preparation of compounds offormula ix.

In Scheme 4, the definition of R is R⁶ as described for the embodimentsof the disclosure. The other variables in Scheme 4 are as described forthe embodiments of the disclosure.

Benzyl amine i can be condensed with methyl 2,2-diethoxyacetimidate togive the 2-aminoquinoline intermediate ii. Intermediate ii can besubjected to Stille coupling with tributyl(1-ethoxyvinyl)stannane toyield iii. Under acidic conditions, iii can be converted to the methylketone iv. The 2-aminoquinoline iv can be diazotized to the2-Chloroquinoline v using sodium nitrite and cuprous chloride.Subsequent addition of alkyl magnesium bromide can yield intermediatevi. Compound vi can be coupled to aryl amines under Pd-catalyzedcoupling conditions to yield vii. Intermediate vii can be treated withTMSN₃ and Indium bromide in dichloromethane to yield the correspondingazide intermediate viii. The azide viii can be reduced under typicalhydrogenation conditions such as Pd and H₂ to give the amine ix whichare examples of MAP4K1 inhibitors described herein.

Scheme 5 shows a synthetic protocol for the preparation of compounds offormula iii.

In Scheme 5, the definition of R is R⁷ as described for the embodimentsof the disclosure. The other variables in Scheme 5 are as described forthe embodiments of the disclosure.

Intermediate i (see Scheme 3 for preparation of intermediate i) can beconverted to the pyridone ii under acidic conditions. Compound ii can becoupled to alkyl amines using a coupling agent such as BOP and DBU inDMF to give the compound iii which are examples of MAP4K1 inhibitorsdescribed herein.

Scheme 6 shows a synthetic protocol for the preparation of compounds offormula vii.

In Scheme 6, the definition of R is R⁷ as described for the embodimentsof the disclosure. The other variables in Scheme 6 are as described forthe embodiments of the disclosure.

The intermediate i (see Scheme 3 for preparation of i) can be reducedunder Staudinger reaction conditions using triphenylphosphine and waterto give amine ii. Conversion to the pyridone iii can be performed underacidic conditions. Subsequent protection of the benzylic amine can bedone with Boc-anhydride and TEA to give intermediate iv. Compound iv canbe coupled to alkyl amines using the coupling agent BOP in DMF to givev. The compound v can be coupled to the aryl amines under Pd-catalyzedcoupling conditions to give vi. The Boc group can be de-protected usingHCl or other acidic conditions to give the amine vii which are examplesof MAP4K1 inhibitors described herein.

Scheme 7 shows a synthetic protocol for the preparation of compounds offormula viii.

Tri-halogen intermediate i (see Intermediate 32 in common intermediatesfor synthesis of intermediate i) can be subjected to Stille couplingwith tributyl(1-ethoxyvinyl)stannane to yield ii. Under acidicconditions, ii can be converted to the methyl ketone iii. Compound iiican be treated with an alcohol using potassium carbonate in methanol toyield intermediate iv. Subsequent addition of alkyl magnesium bromidecan yield intermediate v. Compound v can be treated with TMSN₃ andIndium bromide in dichloromethane to yield the corresponding azideintermediate vi. The azide vi can be coupled to aryl amines underPd-catalyzed coupling conditions to yield vii. Compound vii can bereduced under typical hydrogenation conditions such as Pd and H₂ to givethe amine viii which are examples of MAP4K1 inhibitors described herein.

Scheme 8 shows a synthetic protocol for the preparation of compounds offormula vii.

Tri-halogen intermediate i (see Intermediate 31 in common intermediatesfor synthesis of intermediate i) can be treated with an alcohol or anamine to yield intermediate ii. Intermediate ii can be subjected toPd-catalyzed carbonylation to yield iii. Subsequent addition of alkyllithium or alkyl magnesium bromide can yield intermediate iv. Compoundiv can be treated with TMSN₃ and Indium bromide in dichloromethane toyield the corresponding azide intermediate v. The azide v can be coupledto aryl amines under Pd-catalyzed coupling conditions to yield vi.Compound vi can be reduced under typical hydrogenation conditions suchas Pd and H₂ to give the amine vii which are examples of MAP4K1inhibitors described herein.

Scheme 9 shows a synthetic protocol for the preparation of compounds offormula vi.

The intermediate i (see scheme 3 for preparation of i) can be to thepyridone ii under acidic conditions. Intermediate ii can be treated withPOCl3 to get compound iii which is subsequently reacted with alcoholse.g., oxetan-3-ol, cyclobutanol, methyloxetan-3-ol using potassiumcarbonate to get the 8-alkoxy intermediate iv. Compound iv can becoupled to the aryl amines under Pd-catalyzed coupling conditions togive v. Compound v can be reduced under typical hydrogenation conditionssuch as Pd and H₂ to give the amine vi which are examples of MAP4K1inhibitors described herein.

Scheme 10 shows a synthetic protocol for the preparation of compounds offormula ii.

Intermediate i (see scheme 3 for preparation of intermediate i) can beconverted to the methyl amine ii under one-pot reduction with Pd/C andH2 followed by reductive amination with formaldehyde in MeOH.

Scheme 11 shows a synthetic protocol for the preparation of compounds offormula iv.

The intermediate i (see scheme 3 for preparation of i) can be coupled to(tert-butoxycarbonyl)proline using photoredox catalysis to give compoundii. Compound ii can be coupled to the aryl amines under Pd-catalyzedcoupling conditions to give iii. Compound iii can be de-protected undertypical Boc-deprotection conditions such as HCl to give the amine ivwhich are examples of MAP4K1 inhibitors described herein.

Scheme 12 shows a synthetic protocol for the preparation of compounds offormula v.

The intermediate i can be treated with an organolithium and a ketone oraldehyde to give compound ii. Compound ii can be treated with TMSN3 andindium bromide or boron trifluoride diethyl etherate to give azidecompound iii. Compound iii can be coupled to the aryl chlorides underPd-catalyzed coupling conditions to give iv. Compound iv can be reducedwith Zn and acetic acid to give the amine v which are examples of MAP4K1inhibitors described herein.

Scheme 13 shows a synthetic protocol for the preparation of compounds offormula vi.

The intermediate i can be coupled to a boronate under Pd catalysis togive compound ii. Compound ii can be treated with an oxidizing reagentsuch as m-CPBA to give the epoxide compound iii. Compound iii can betreated with TMSN3 and indium bromide or boron trifluoride diethyletherate to give azide compound iv. Compound iv can be coupled to thearyl amines under Pd-catalyzed coupling conditions to give v. Compound vcan be reduced with hydrogen under Pd-catalyzed conditions to give theamine vi which are examples of MAP4K1 inhibitors described herein.

Scheme 14 shows a synthetic protocol for the preparation of compounds offormula iv.

The intermediate i can reduced with Zn and acetic acid amine compoundii. Compound ii can be treated with a ketone e.g., oxetan-3-one oraldehyde under reductive amination conditions such as sodiumcyanoborohydride to give substituted amine compound iii. Compound iiican can be coupled to the aryl amines under Pd-catalyzed couplingconditions to give iv which are examples of MAP4K1 inhibitors describedherein.

Scheme 15 shows a synthetic protocol for the preparation of compounds offormula v.

The intermediate i can reduced with Zn and acetic acid amine compoundii. Compound ii can be treated with a haloacetate compound such asmethyl bromoacetate substituted amine compound iii. Compound iii can bereduced with LiBH₄ to give amino alcohol compound iv. Compound iv cancan be coupled to the aryl amines under Pd-catalyzed coupling conditionsto give v which are examples of MAP4K1 inhibitors described herein.

Scheme 16 shows a synthetic protocol for the preparation of compounds offormula iii.

The intermediate i can be coupled to the aryl amines under Pd-catalyzedcoupling conditions to give ii. Compound ii can be reduced with hydrogenunder Pd-catalyzed conditions to give the amine iii which are examplesof MAP4K1 inhibitors described herein.

Scheme 17 shows a synthetic protocol for the preparation of compounds offormula vi.

The intermediate i can be coupled to the aryl amines under Pd-catalyzedcoupling conditions to give ii. Compound ii can be deprotected underacidic conditions such as HCl to give the amine iii which are examplesof MAP4K1 inhibitors described herein.

The following examples are intended to be illustrative and are not meantin any way to be limiting.

EXEMPLIFICATION Abbreviations

BOP (1H-Benzotriazol-1-yloxy)[tris(dimethylamino)]phosphoniumhexafluorophosphate

C Celsius

DAST Diethylaminosulfur trifluoride

DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene

DCE dichloroethane

DCM dichloromethane

DEA diethyl amine

DIPEA diisopropylamine

DMF dimethyl formamide

DMAP 4-Dimethylaminopyridine

DMB 3,3-Dimethyl-1-butanol

DMSO dimethylsulfoxide

EA ethyl acetate

EtOH ethanol

h hour(s)

HPLC high performance liquid chromatography

IC50 inhibitory concentration 50%

IPA isopropyl alcohol

min minutes

MTBE methyl tert-butyl ether

MCCN acetonitrile

MeOH methanol

NMP N-Methyl-2-pyrrolidone

PE petroleum ether

rt room temperature

TEA triethylamine

THE tetrahydrofuran

TFA trifluoroacetic acid

LC-MS: Unless otherwise indicated, all liquid chromatography-massspectrometry (LC-MS) data (sample analyzed for purity and identity) wereobtained with an Agilent model-1260 LC system using an Agilent model6120 mass spectrometer utilizing ES-API ionization fitted with anAgilent Poroshel 120 (EC-C18, 2.7 um particle size, 3.0×50 mmdimensions) reverse-phase column at 22.4 degrees Celsius. The mobilephase consisted of a mixture of solvent 0.1% formic acid in water and0.1% formic acid in MCCN. A constant gradient from 95% aqueous/5%organic to 5% aqueous/95% organic mobile phase over the course of 4minutes was utilized. The flow rate was constant at 1 mL/min.

Prep LC-MS: Preparative HPLC was performed on a Shimadzu Discovery VP®Preparative system fitted with a Luna 5u C18(2) 100A, AXIA packed,250×21.2 mm reverse-phase column at 22.4 degrees Celsius. The mobilephase consisted of a mixture of solvent 0.1% formic acid in water and0.1% formic acid in MCCN. A constant gradient from 95% aqueous/5%organic to 5% aqueous/95% organic mobile phase over the course of 25minutes was utilized. The flow rate was constant at 20 mL/min. Reactionscarried out in a microwave were done so in a Biotage Initiator microwaveunit.

Silica gel chromatography: Silica gel chromatography was performed oneither a Teledyne Isco CombiFlash® Rf unit or a Biotage® Isolera Fourunit.

Proton NMR: Unless otherwise indicated, all ¹H NMR spectra were obtainedwith a Varian 400 MHz Unity Inova 400 MHz NMR instrument (acquisitiontime=3.5 seconds with a 1 second delay; 16 to 64 scans). Wherecharacterized, all protons were reported in DMSO-d6 solvent as parts-permillion (ppm) with respect to residual DMSO (2.50 ppm).

One of ordinary skill in the art will recognize that modifications ofthe gradient, column length, and flow rate are possible and that someconditions may be more suitable for compound characterization thanothers, depending on the chemical species being analyzed.

Synthesis of Intermediates

I. Synthesis of arylamine intermediates

Intermediate 1: 2-(2-Fluoropropan-2-yl)pyrimidin-4-amine

Step 1: Ethyl 4-aminopyrimidine-2-carboxylate

Triethylamine (285 g, 2.81 mol, 2.00 equiv) was added dropwise to a asolution of ethyl 2-amino-2-iminoacetate hydrochloride (215 g, 1.41 mol,1.00 equiv) and 2-chloroprop-2-enenitrile (112 mL, 1.41 mol, 1.00 eq) inEtOH (1.8 L) at 0° C. The mixture was allowed to warm to 25° C. andstirred at 25° C. for 6 h. The reaction mixture was concentrated and theresidue was partitioned between water (10.0 L) and EA (5.0 L). Thelayers were separated, and the aqueous layer was extracted with EA (5.0L×2). The organic layers were combined and dried over Na₂SO₄. The driedsolution was filtered, and the filtrate was concentrated to give thetitle compound (270 g, crude) as a dark brown solid.

Step 2: 2-(4-Aminopyrimidin-2-yl)propan-2-ol

Methylmagnesium bromide (900 mL, 3.0 M, 5.0 eq) was added to a solutionof ethyl 4-aminopyrimidine-2-carboxylate (90.0 g, 538 mmol, 1.00 eq) in2-Me THE (1.00 L) at −20° C. The reaction mixture was allowed warm to 0°C. and stirred at that temperature for 1 h. The reaction mixture wasdiluted with saturated aqeuous ammonium chloride solution (10.0 L) andthe aqueous layer was extracted with EA (3.0 L×4). The organic layerswere combined and dried over Na₂SO₄, and the dried solution wasfiltered. The filtrate was concentrated to give the title compound (50g, crude) as a dark brown solid.

Step 3: 2-(2-Fluoropropan-2-yl)pyrimidin-4-amine

DAST (414 mL, 3.13 mol, 10.0 eq) was added to a solution of2-(4-aminopyrimidin-2-yl)propan-2-ol (48.0 g, 313 mmol, 1.00 eq) in DCM(1.30 L) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h,and then was diluted with water (4.50 L). The reaction mixture wasadjusted to pH=7-8 with aqueous sodium hydroxide solution (0.50 L) andsodium carbonate solution (200 mL), then was extracted with EA (2.00L×3). The organic layers were combined and dried over Na₂SO₄, and thedried solution was filtered and concentrated. The residue was purifiedby rp-HPLC (neutral condition) to give the title compound (13.0 g) as awhite solid. ¹H NMR (400 MHz DMSO-d6) δ 8.05-8.07 (d, J=5.6 Hz), 6.93(s, 1H), 6.32-6.33 (d, J=5.6 Hz, 1H), 1.63 (s, 3H), 1.58 (s, 3H).

Intermediate 2:2-Amino-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

Step 1: 7,7-Dimethyl-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-2-one

A mixture of 2,2-dimethyltetrahydro-4H-pyran-4-one (500 g, 3.90 mol,1.00 eq) and pyrrolidine (391 mL, 4.68 mol, 1.20 eq) in toluene (4.00 L)was heated at 145° C. with a Dean-Stark trap for 2 h. The water layer(˜16 mL) was removed from the Dean-Stark trap and the reaction mixturewas cooled to 15° C. After cooling, prop-2-ynamide (539 g, 7.80 mol,2.00 eq) was added and the reaction mixture was heated to 150° C. Thereaction mixture was heated at 150° C. for 10 h, then was cooled toambient temperature. The cooled reaction mixture was filtered and thefiltrate was concentrated under reduced pressure to give a residue. Theresidue was purified by flash-column chromatography on silica gel (10%methanol-dichloromethane) to give the title compound (560 g, 62% yield)as a yellow solid.

Step 2: 2-Chloro-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine

A solution of7,7-dimethyl-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-2-one (500 g,2.23 mol, 1 eq) in POCl₃ (350 mL, 3.77 mol, 9.64 eq) was heated to 100°C. for 6 h. The reaction mixture then cooled to ambient temperature andconcentrated under vacuum. The residue was poured over ice-water (1.00L). The mixture was extracted with EA (750 mL×2). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated under vacuum togive the title compound (363 g, 82.2% yield) as a brown oil.

Step 3: 2-Chloro-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

A solution of NaIO₄ (487 g, 2.28 mol, 3.00 eq) in water (1.20 L) asadded to a mixture of2-chloro-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine (150 g, 759mmol, 1.00 eq) in MeCN (50.0 mL) and CCl₄ (2.70 L). The mixture wascooled to 0° C., and then RuCl₃ (11.0 g, 53.1 mmol, 0.07 eq) was added.The reaction mixture was stirred at 0° C. for 0.5 h, then was warmed to20° C. for 11.5 h. Saturated aqeuous sodium sulfite solution (1.00 L)was added, and the mixture was filtered. The filtrate was extracted withEA (500 mL×3), and the organic layers were combined. The combinedorganic layer was washed with brine (1.00 L), dried over Na₂SO₄,filtered and concentrated to give the title compound (132 g, 624 mmol,82.1% yield) as a yellow solid.

Step 4:2-((2,4-Dimethoxybenzyl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

(2,4-Dimethoxyphenyl) methanamine (160 g, 957 mmol, 1.50 eq) was addedto a solution of2-chloro-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (135 g,638 mmol, 1.00 eq) and DIPEA (222 mL, 1.28 mol, 2.00 eq) in NMP (1.08 L)at ambient temperature. The reaction mixture was heated to 140° C. for 2h, and then was cooled to ambient temperature. The reaction mixture waspartitioned between water (700 mL) and EA. The layers were separated,and the aqueous layer was further extracted with EA (500 mL×3). Theorganic layers were combined and washed with brine (400 mL×3), driedover anhydrous sodium sulfate, filtered and concentrated to afford thetitle compound as a yellow solid (160 g). The crude product was used fornext step directly.

Step 5: 2-Amino-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

HCl (4.0 M in dioxane, 1.20 L, 11.0 equiv) was added to:2-((2,4-dimethoxybenzyl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(150 g, 438 mmol, 1.00 eq) at 20° C. The reaction mixture was heated to60° C. for 2 h, then was cooled to ambient temperature and concentratedunder vacuum. The residue was poured into saturated NaHCO₃ aqueoussolution (1.00 L) and extracted with EA (500 mL×4). The combined organiclayer was washed with brine (500×2), dried over Na₂SO₄, filtered andconcentrated. The residue was dissolved in EA (300 mL) and petroleumether (150 mL) was added drop wise to get yellow slurry. The solids werefiltered and collected to give the title compound (52.0 g, 60.9% yield)as a yellow solid. MS (ES+) C₁₀H₁₂N₂O₂ requires: 192, found: 193[M+H]⁺.¹H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J=8.4 Hz, 1H), 6.98 (s, 2H), 6.39(d, J=8.8 Hz, 1H), 2.89 (s, 2H), 1.37 (s, 6H).

Intermediates 3 and 4: (S)-6-Amino-2-(sec-butyl)pyridazin-3(2H)-one and(R)-6-Amino-2-(sec-butyl)pyridazin-3(2H)-one

each of which is represented by one of the structures shown below:

Step 1: 2-(sec-Butyl)-6-chloropyridazin-3(2H)-one

Potassium carbonate (15.6 g, 113 mmol, 3.05 equiv) was added to asolution of 6-chloropyridazin-3(2H)-one (5.00 g, 38.3 mmol, 1.00 equiv)and 2-bromobutane (5.17 g, 37.7 mmol, 0.98 equiv) in DMF (80 mL). Themixture was stirred at 80° C. for 4 h, then was cooled to ambienttemperature. The cooled reaction mixture was partitioned between waterand dichloromethane, and the layers were separated. The aqueous layerwas further extracted with dichlormethane (200 mL×2), and the layerswere combined. The combined organic layers were washed with brine anddried over anhydrous sodium sulfate. The dried solution was filtered,and the filtrate was concentrated under reduced pressure to give thetitle compound (5.90 g, crude) as a yellow oil that was used for nextstep directly.

Step 2: 2-(sec-Butyl)-6-((diphenylmethylene)amino)pyridazin-3(2H)-one

XantPhos (3.53 g, 6.11 mmol, 0.200 equiv), Pd(dba)₂ (1.76 g, 3.05 mmol,0.100 equiv) and cesium carbonate (24.9 g, 76.4 mmol, 2.50 equiv) wereadded to a solution of 2-(sec-Butyl)-6-chloropyridazin-3(2H)-one (5.70g, 30.5 mmol, 1.00 equiv) and diphenylmethanimine (6.09 g, 33.6 mmol,1.10 equiv) in dioxane (80 mL). The mixture was degassed and purged withN₂ three times, and then heated to 100° C. for 4 h. The reaction mixturewas cooled to ambient temperature, diluted with water and extracted withEA three times. The combined organic layers were dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure to givea residue. The residue was purified by flash-column chromatography onsilica gel (gradient elution, 0% to 67% EA-petroleum ether) to give thetitle compound (1.80 g, 18% yield) as a yellow oil.

Step 3: 6-Amino-2-(sec-butyl)pyridazin-3(2H)-one

HCl (aqueous, 6 M, 2.01 mL) was added to a solution of2-(sec-butyl)-6-((diphenylmethylene)amino)pyridazin-3(2H)-one (0.80 g,2.4 mmol) in tetrahydrofuran (100 mL) at 25° C. The reaction mixture wasstirred at 25° C. for 0.5 h. The reaction mixture was diluted with water(100 mL) and extracted with EA (50 mL×3). The combined organic layerswere dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to give a residue. The residue was purified byflash-column chromatography on silica gel (gradient elution, 0% to 100%EA-petroleum ether) to give the title compound (190 mg, 47% yield) as awhite solid. MS (ES+) C₈H₁₃N₃O requires: 167, found: 168[M+H]⁺.

Step 4: (S)-6-Amino-2-(sec-butyl)pyridazin-3(2H)-one and(R)-6-Amino-2-(sec-butyl)pyridazin-3 (2H)-one

6-Amino-2-(sec-butyl)pyridazin-3(2H)-one (190 mg, 1.14 mmol) wasseparated by SFC (column: DAICEL CHIRALPAK IC (250 mm×30 mm, 5 um);mobile phase: [0.5% DEA in MeOH/CO₂]; Gradient: 5%-20%. One of (R orS)-6-Amino-2-(sec-butyl)pyridazin-3(2H)-one (1^(st) eluting isomer,Intermediate 3, 60.0 mg, 31%) was obtained as a yellow solid, MS (ES+)C₈H₁₃N₃O requires: 167, found: 168[M+H]⁺. The remaining one of (R orS)-6-Amino-2-(sec-butyl)pyridazin-3(2H)-one (2^(nd) eluting isomer,Intermediate 4, 70.0 mg, 37% yield) was obtained as a yellow solid, MS(ES+) C₈H₁₃N₃O requires: 167, found: 168[M+H]⁺.

Intermediate 5: 2-Amino-7,8-dihydro-1,6-naphthyridin-5(6H)-one

Steps 1 and 2

2-Amino-7,8-dihydro-1,6-naphthyridin-5(6H)-one was prepared from2-chloro-7,8-dihydro-1,6-naphthyridin-5(6H)-one using the same two-stepprocedure as described in Steps 4 and 5 in the preparation ofIntermediate 2. MS (ES+) C₈H₉N₃O requires: 163, found: 164[M+H]⁺.

Intermediate 6: 2-Isopropoxypyrimidin-4-amine

Step 1: 2-Isopropoxypyrimidin-4-amine

Sodium hydride (60% dispersion in oil, 617 mg, 15.4 mmol, 2.00 equiv)was added to a mixture of propan-2-ol (696 mg, 11.6 mmol, 1.50 equiv) intetrahydrofuran (10 mL) at 0° C. The mixture was stirred at 25° C. for 1h, 2-chloropyrimidin-4-amine (1.00 g, 7.72 mmol) was added and themixture was heated to 60° C. After stirring for 12 h, the reactionmixture was cooled to ambient temperature and quenched by addition ofwater (20 mL). The quenched mixture was extracted with EA (20 mL×3), andthe layers were combined. The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to give a residue. The residue was purified by reverse phaseprep-HPLC (column: Xtimate C18 150*25 mm*5 um; mobile phase: [water(0.05% ammonia hydroxide v/v)-MECN]; B %: 0%-30%, 10 min) to give thetitle compound (140 mg, 12% yield) as a white solid. ¹H-NMR (400 MHz,DMSO-d6): δ ppm 7.93 (d, J=6.0 Hz, 1H), 7.37 (s, 2H), 6.38 (d, J=6.0 Hz,1H), 5.08 (td, J=6.4, 12.3 Hz, 1H), 1.22 (d, J=6.0 Hz, 6H).

Intermediates 7 and 8: (S)-6-Amino-2-(sec-butyl)nicotinonitrile and(R)-6-Amino-2-(sec-butyl)nicotinonitrile

each of which is represented by one of the structures shown below:

which is represented by one of the structures shown below:

Step 1: 6-Amino-2-(but-1-en-2-yl)nicotinonitrile

Potassium carbonate (3.24 g, 23.4 mmol, 2.00 equiv) and Pd(PPh₃)₄ (1.35g, 1.17 mmol, 0.10 eq) were added to a mixture of6-amino-2-chloronicotinonitrile (1.80 g, 11.7 mmol, 1.00 equiv) and2-(but-1-en-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.30 g, 12.6mmol, 1.08 equiv) in dioxane (20 mL) and water (4 mL). The mixture wasstirred at 100° C. for 12 h under nitrogen. The mixture was then cooledto ambient temperature and partitioned between water (50 mL) and EA (65mL). The layers were separated, and the aqueous layer was furtherextracted with EA (65 mL×2). The layers were combined, and the combinedlayers were dried over anhydrous sodium sulfate, filtered andconcentrated to give a residue. The residue was purified by flash-columnchromatography on silica gel (gradient elution, 10% to 25% EA-petroleumether) to give the title compound (1.50 g, 63% yield) as a white solid.

Step 2: 6-Amino-2-(sec-butyl)nicotinonitrile

Palladium on carbon (10 wt %, 300 mg, 0.282 mmol) was added to a mixtureof 6-amino-2-(but-1-en-2-yl)nicotinonitrile (1.50 g, 8.66 mmol, 1.00equiv) in methanol (50 mL). The mixture was stirred at 25° C. for 16 hunder hydrogen atmosphere (15 psi), and then was filtered throughcelite. The filtrate was concentrated under reduced pressure to give aresidue. The residue was purified by flash-column chromatography onsilica gel (gradient elution, 5% to 10% EA-petroleum ether) to give thetitle compound (950 mg, 63% yield) as a yellow solid.

Step 3: tert-ButylN-[6-(butan-2-yl)-5-cyanopyridin-2-yl]-N-[(tert-butoxy)carbonyl]carbamate

Di-tert-butyl dicarbonate (2.12 g, 9.70 mmol, 2.00 equiv) and DMAP (59.3mg, 0.485 mmol, 0.100 equiv) were added to a mixture of6-amino-2-(sec-butyl)nicotinonitrile (850 mg, 4.85 mmol, 1.00 equiv) andtriethylamine (982 mg, 9.70 mmol, 2.00 equiv) in dichloromethane (15mL). The reaction mixture was stirred at 20° C. for 2 h, and then water(20 mL) was added the resulting mixture was extracted with EA (25 mL×3).The organic layers were combined and dried over anhydrous sodiumsulfate. The dried solution was filtered and concentrated to give aresidue. The residue was purified by flash-column chromatography onsilica gel (gradient elution, 1% to 10% EA-petroleum ether) to give thetitle compound (1.15 g, 80% yield) as a colorless oil.

Step 4: tert-ButylN-{6-[(2S)-butan-2-yl]-5-cyanopyridin-2-yl}-N-[(tert-butoxy)carbonyl]carbamateand tert-ButylN-{6-[(2R)-butan-2-yl]-5-cyanopyridin-2-yl}-N-[(tert-butoxy)carbonyl]carbamate

tert-ButylN-[6-(butan-2-yl)-5-cyanopyridin-2-yl]-N-[(tert-butoxy)carbonyl]carbamate(950 mg, 2.53 mmol) was separated by SFC (column: DAICEL CHIRALPAK IC(250 mm*30 mm, um); mobile phase: [IPA gradient in CO₂ with 0.5% DEA];to give two peaks separately. Absolute stereochemistry of the separatedenantiomers was arbitrarily assigned. 1^(st) eluting isomer (340 mg, 34%yield) and second eluting isomer 400 mg, 42% yield) were obtained ascolorless oils.

Step 5: one of (R or S)-6-Amino-2-(sec-butyl)nicotinonitrile

HCl (4.0 M in dioxane, 10.0 mL), was added to one of tert-butylN-{6-[(2R orS)-butan-2-yl]-5-cyanopyridin-2-yl}-N-[(tert-butoxy)carbonyl]carbamate(second eluting isomer, 400 mg, 1.07 mmol) in dioxane (2 mL). Thereaction mixture was stirred at 20° C. for 15 h, then was partitionedbetween saturated aqueous sodium bicarbonate solution (30 mL) and EA (35mL). The layers were separated, and the aqueous layer was furtherextracted with EA (35 mL×2). The organic layers were combined and driedover anhydrous sodium sulfate. The dried solution was filtered andconcentrated to give a residue. The residue was purified by flash-columnchromatography on silica gel (gradient elution, 5% to 25% EA-petroleumether) to give the title compound ((Intermediate 7, 160 mg, 78% yield)as a yellow oil. MS (ES+) C₁₀H₁₃N₃ requires: 175, found: 176[M+H]⁺.¹H-NMR (400 MHz, CDCl₃): δ ppm 7.56 (d, J=8.4 Hz, 1H), 6.32 (d, J=8.4Hz, 1H), 4.87 (s, 2H), 3.17-3.08 (m, 1H), 1.83-1.71 (m, 1H), 1.62-1.54(m, 1H), 1.24 (d, J=6.4 Hz, 3H), 0.86 (t, J=7.2 Hz, 3H).

Step 6: The remaining one of (R orS)-6-Amino-2-(sec-butyl)nicotinonitrile

The title compound (Intermediate 8) was prepared from the remaining oneof tert-butyl N-{6-[(2R orS)-butan-2-yl]-5-cyanopyridin-2-yl}-N-[(tert-butoxy)carbonyl]carbamate(first eluting isomer) using the same procedure as described in Step 5.MS (ES+) C₁₀H₁₃N₃ requires: 175, found: 176[M+H]⁺. ¹H-NMR (400 MHz,CDCl₃): δ ppm 7.56 (d, J=8.4 Hz, 1H), 6.32 (d, J=8.4 Hz, 1H), 4.87 (s,2H), 3.17-3.08 (m, 1H), 1.83-1.71 (m, 1H), 1.62-1.54 (m, 1H), 1.24 (d,J=6.4 Hz, 3H), 0.86 (t, J=7.2 Hz, 3H).

Intermediate 9: 2-Amino-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one

Steps 1 and 2

2-Amino-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one was prepared from2-chloro-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one using the sametwo-step procedure as described in Steps 4 and 5 in the preparation ofIntermediate 2. MS (ES+) C₁₁H₁₄N₂O requires: 190, found: 191 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6): δ ppm 7.75 (d, J=8.8 Hz, 1H), 6.88 (s, 2H), 6.34(d, J=8.8 Hz, 1H), 2.66 (s, 2H), 2.33 (s, 2H), 0.99 (s, 6H).

Intermediate 10:2-Amino-7,7-dimethyl-7,8-dihydro-5H-pyrano[3,4-b]pyrazin-5-one

Step 1: Methyl5-methoxy-3-(2-methylprop-1-en-1-yl)pyrazine-2-carboxylate

Potassium phosphate (7.23 g, 34.1 mmol, 2.99 equiv) and XPhos (G3precatalyst) (480 mg, 568 μmol, 0.05 equiv) were added to a mixture ofmethyl 3-chloro-5-methoxypyrazine-2-carboxylate (2.30 g, 11.4 mmol, 1.00equiv) and4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxaborolane (3.10g, 17.0 mmol, 1.49 equiv) in tetrahydrofuran (25 mL) and water (3 mL).The reaction mixture was stirred at 50° C. for 4 h under nitrogen. Thereaction mixture was then cooled to ambient temperature and concentratedto give a residue. The residue was purified by flash-columnchromatography on silica gel (gradient elution, 5% to 50% EA-petroleumether) to give the title compound (2.00 g, 79% yield) as a white solid.

Step 2: 5-Methoxy-3-(2-methylprop-1-en-1-yl)pyrazine-2-carboxylic acid

LiOH (1.51 g, 63.0 mmol, 5.00 equiv) was added to a mixture of methyl5-methoxy-3-(2-methylprop-1-en-1-yl)pyrazine-2-carboxylate (2.80 g, 12.6mmol, 1.00 equiv) in methanol (50 mL). The reaction mixture was stirredat 20° C. for 2 h, and then was diluted with water (100 ml). Aqueous HCl(2 N) was added to the mixture until the pH was 7, and then the mixturewas extracted with EA (50 mL×3). The combined organic layers were driedwith anhydrous sodium sulfate, filtered and concentrated in vacuo togive the title compound (2.40 g, crude) as a white solid.

Step 3: 2-Methoxy-7,7-dimethyl-7,8-dihydro-5H-pyrano[3,4-b]pyrazin-5-one

Trimethylsilyl trifluoromethanesulfonate (19.1 mL, 106 mmol, 10.0 equiv)was added to a mixture of5-methoxy-3-(2-methylprop-1-en-1-yl)pyrazine-2-carboxylic acid (2.20 g,10.6 mmol) in DCM (10 mL). The reaction mixture was stirred at 20° C.for 72 h, then was poured slowly into saturated aqueous sodiumbicarbonate solution (80 mL). The mixture was extracted with EA (50mL×3). The combined organic layers were dried with anhydrous sodiumsulfate, filtered and concentrated in vacuo to give a residue. Theresidue was purified by flash-column chromatography on silica gel(gradient elution, 10% to 30% EA-petroleum ether) to give the titlecompound (1.00 g, 45% yield) as a yellow solid.

Step 4: 2-Hydroxy-7,7-dimethyl-7,8-dihydro-5H-pyrano[3,4-b]pyrazin-5-one

A mixture of2-methoxy-7,7-dimethyl-7,8-dihydro-5H-pyrano[3,4-b]pyrazin-5-one (1.00g, 4.80 mmol, 1.00 equiv) in pyridine hydrochloride (2.78 g, 24.0 mmol,5.00 equiv) was stirred at 150° C. for 1 h. The reaction mixture wasthen poured onto water (60 mL) and extracted with EA (50 mL×3). Thecombined organic layers were dried with anhydrous sodium sulfate,filtered and concentrated in vacuo. The residue was purified byprep-HPLC (column: Xtimate C18 10μ 250 mm*80 mm; mobile phase: [water(0.05% ammonia hydroxide v/v)-MECN]; B %: 0%-7%, 6.5 min) to give thetitle compound (600 mg, 64% yield) as a white solid.

Step 5: 2-Chloro-7,7-dimethyl-7,8-dihydro-5H-pyrano[3,4-b]pyrazin-5-one

A mixture of2-hydroxy-7,7-dimethyl-7,8-dihydro-5H-pyrano[3,4-b]pyrazin-5-one (100mg, 515 μmol) in phosphorus oxychloride (3 mL) was stirred at 100° C.for 1 h. After cooling to ambient temperature, the reaction mixture waspoured onto saturated aqueous sodium bicarbonate solution (10 mL), andthen extracted with EA (30 mL×3). The combined organic layers were driedwith anhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by flash-column chromatography on silica gel(gradient elution, 20% to 50% EA-petroleum ether) to give the titlecompound (110 mg, crude) as a yellow solid.

Steps 6 and 7:2-Amino-7,7-dimethyl-7,8-dihydro-5H-pyrano[3,4-b]pyrazin-5-one

The title compound was prepared from2-chloro-7,7-dimethyl-7,8-dihydro-5H-pyrano[3,4-b]pyrazin-5-one usingthe same two-step procedure as described in Steps 4 and 5 in thepreparation of Intermediate 2. ¹H NMR (400 MHz, CDCl₃): δ ppm 7.93 (s,1H), 7.21 (d, J=8.4 Hz, 1H), 6.48 (d, J=2.0 Hz, 1H), 6.46-6.44 (m, 1H),6.43 (m, 1H), 4.57 (d, J=5.6 Hz, 2H), 3.82-3.78 (m, 6H), 3.05 (s, 2H),1.50 (s, 6H).

Intermediate 11: 2-Amino-7,7-dimethylfuro[3,4-b]pyridin-5(7H)-one

Step 1: Methyl 6-methoxy-2-(prop-1-en-2-yl)nicotinate

Pd(dppf)Cl₂ (544 mg, 744 umol, 0.500 equiv) and cesium fluoride (4.52 g,29.8 mmol, 2.00 equiv) were added to a mixture of methyl2-chloro-6-methoxynicotinate (3.00 g, 14.9 mmol) and4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (3.75 g, 22.3mmol) in MeCN (50 mL). The mixture was stirred at 70° C. for 2 h undernitrogen atmosphere, then was cooled to ambient temperature. Thereaction mixture was then poured onto water (200 mL) and extracted withEA (50 mL×3). The combined organic layers were dried over anhydroussodium sulfate, filtered and concentrated in vacuo to give a residue.The residue was purified by flash-column chromatography on silica gel(gradient elution, 1% to 2% EA-petroleum ether) to give the titlecompound (3.0 g, crude) as a colorless oil.

Step 2: 2-Methoxy-7,7-dimethylfuro[3,4-b]pyridin-5(7H)-one

A solution of Methyl 6-methoxy-2-(prop-1-en-2-yl)nicotinate (3.00 g,14.5 mmol) in TfOH (17.0 g, 113 mmol, 10 mL) was stirred at 25° C. for12 h. The reaction mixture was then poured over water (50 mL) andsaturated aqueous sodium bicarbonate solution was added to adjust the pHto 7. The mixture was extracted with EA (30 mL×3). The combined organiclayers were dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give a residue. The residue was purified byflash-column chromatography on silica gel (gradient elution, 10% to 33%EA-petroleum ether) to give the title compound (2.3 g, 82% yield) as ayellow solid.

Steps 3-6: 2-Amino-7,7-dimethylfuro[3,4-b]pyridin-5(7H)-one

The title compound was prepared from2-Methoxy-7,7-dimethylfuro[3,4-b]pyridin-5(7H)-one using the two-stepprocedure described in Steps 4 and 5 for Intermediate 10, followed bythe two-step procedure as described in Steps 4 and 5 in the preparationof Intermediate 2. MS (ES+) C₉H₁₀N₂O₂ requires: 178, found: 179[M+H]⁺.

Intermediates 12 and 13:(6aR,9aR)-2-amino-7,8,9,9a-tetrahydrocyclopenta[5,6]pyrano[4,3-b]pyridin-5(6aH)-oneand(6aS,9aS)-2-amino-7,8,9,9a-tetrahydrocyclopenta[5,6]pyrano[4,3-b]pyridin-5(6aH)

each of which is represented by one of the structures shown below:

which is represented by one of the structures shown below:

which is represented by one of the structures shown below:

Step 1: Methyl 2-(cyclopent-1-en-1-yl)-6-methoxynicotinate

Cesium fluoride (5.27 g, 34.7 mmol, 1.99 equiv) and Pd(dppf)Cl₂ (1.27 g,1.74 mmol, 0.100 equiv) were added to a mixture of methyl2-chloro-6-methoxynicotinate (3.50 g, 17.4 mmol, 1.00 equiv) and2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.05 g,26.0 mmol, 1.49 equiv) in MCCN (100 mL) and water (5 mL). The reactionmixture was stirred at 75° C. for 2 h, then was cooled to ambienttemperature and concentrated to give a residue. The residue was purifiedby flash-column chromatography on silica gel (gradient elution, 5% to20% EA-petroleum ether) to give the title compound (3.77 g, 93% yield)as a colorless oil.

Step 2:2-Methoxy-7,8,9,9a-tetrahydrocyclopenta[5,6]pyrano[4,3-b]pyridin-5(6aH)-one

The title compound was prepared from methyl2-(cyclopent-1-en-1-yl)-6-methoxynicotinate using the same proceduredescribed in Step 2 of Intermediate 11.

Steps 3-4:2-Chloro-7,8,9,9a-tetrahydrocyclopenta[5,6]pyrano[4,3-b]pyridin-5(6aH)-one

The title compound was prepared from2-Methoxy-7,8,9,9a-tetrahydrocyclopenta[5,6]pyrano[4,3-b]pyridin-5(6aH)-oneusing the same two-step procedure described in Steps 4 and 5 forIntermediate 10.

Step 5:(6aR,9aR)-2-Chloro-7,8,9,9a-tetrahydrocyclopenta[5,6]pyrano[4,3-b]pyridin-5(6aH)-oneand(6aS,9aS)-2-chloro-7,8,9,9a-tetrahydrocyclopenta[5,6]pyrano[4,3-b]pyridin-5(6aH)-one

2-Chloro-7,8,9,9a-tetrahydrocyclopenta[5,6]pyrano[4,3-b]pyridin-5(6aH)-one(1.5 g, 6.71 mmol) was separated by SFC (Chiralpak AD-3, MeOH gradientin CO₂ with 0.5% DEA) to give two peaks separately. The first elutingisomer (720 mg, 48% yield) and second eluting isomer 750 mg, 50% yield)were obtained as white solids.

Steps 6 and 7: One of (6aR,9aR)- or(6aS,9aS)-2-Amino-7,8,9,9a-tetrahydrocyclopenta[5,6]pyrano[4,3-b]pyridin-5(6aH)-one

The title compound (Intermediate 12) was prepared from one of (6aR,9aR)-or(6aS,9aS)-2-Chloro-7,8,9,9a-tetrahydrocyclopenta[5,6]pyrano[4,3-b]pyridin-5(6aH)-one(first eluting isomer from step 5) using the same two-step procedure asdescribed in Steps 4 and 5 for Intermediate 2. MS (ES+) C₁₁H₁₂N₂O₂requires: 204, found: 205[M+H]⁺

Steps 8 and 9: The remaining one of (6aR,9aR)- or(6aS,9aS)-22-Amino-7,8,9,9a-tetrahydrocyclopenta[5,6]pyrano[4,3-b]pyridin-5(6aH)-one

The title compound (Intermediate 13) was prepared from the remaining oneof (6aR,9aR)- or(6aS,9aS)-22-chloro-7,8,9,9a-tetrahydrocyclopenta[5,6]pyrano[4,3-b]pyridin-5(6aH)-one(second eluting isomer from step 5) using the same two-step procedure asdescribed in Steps 4 and 5 for Intermediate 2. MS (ES+) C₁₁H₁₂N₂O₂requires: 204, found: 205[M+H]⁺

Intermediate 14: 2-Amino-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

Step 1: 2-Amino-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

The title compound was prepared from tetrahydro-4H-pyran-4-one using thesame five-step procedure described in Steps 1-5 for Intermediate 2. MS(ES+) C₈H₈N₂O₂ requires: 164, found: 165[M+H]⁺. ¹H NMR, 400 MHz,DMSO-d6, δ=7.77 (d, J=8.8 Hz, 1H), 7.01 (s, 2H), 6.41 (d, J=8.8 Hz, 1H),4.44-4.41 (m, 2H), 2.88-2.85 (m, 2H).

Intermediate 15:2-Amino-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

Step 1: 2-Methoxy-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

BH₃-Me₂S (10 M, 5.31 mL, 53.1 mmol, 1.10 equiv) was added dropwise to asolution of methyl 6-methoxy-2-(prop-1-en-2-yl)nicotinate (10.0 g, 48.3mmol, 1.00 eq) in THE (100 mL) at 0° C. The mixture was warmed to 20° C.and stirred at that temperature for 2 h. The reaction mixture was thencooled to 0° C. and NaHCO₃ (20.3 g, 241 mmol, 5.00 eq) in water (35.0mL) and H₂O₂ (30% in water, 69.6 mL, 724 mmol, 15.0 eq) were addeddropwise. The reaction mixture was stirred at 20° C. for 30 min and at30-45° C. for 12 h. The reaction mixture was then poured into saturatedaqeuous Na₂SO₃ solution (200 mL) and extracted with EA (50.0 mL×3). Theorganic layers were combined and washed with brine (200 mL), dried overNa₂SO₄, filtered and concentrated. The residue was purified byflash-column chromatography on silica gel (gradient elution, 5% to 15%EA-petroleum ether) to give the title compound (15.0 g, 77.6 mmol, 80.4%yield) as yellow solid.

Steps 2-5: -Amino-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

The title compound was prepared from2-methoxy-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one using thetwo-step procedure described in Steps 4 and 5 for Intermediate 10,followed by the two-step procedure as described in Steps 4 and 5 in thepreparation of Intermediate 2. MS (ES+) C₉H₁₀N₂O₂ requires: 178, found:179[M+H]⁺. ¹H NMR: 400 MHz, DMSO-d6 δ 7.76 (d, J=8.6 Hz, 1H), 7.01 (s,2H), 6.40 (d, J=8.6 Hz, 1H), 4.44 (dd, J=11.2 Hz, 4.4 Hz, 1H), 4.12 (dd,J=11.0 Hz, 6.8 Hz, 1H), 2.93 (td, J=7.0 Hz, 4.4 Hz, 1H), 1.20 (d, J=7.0Hz, 3H).

Intermediate 16:2-Amino-7-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

Step 1: Methyl (E)-6-methoxy-2-(prop-1-en-1-yl)nicotinate

A mixture methyl 2-chloro-6-methoxynicotinate (25.0 g, 148 mmol, 1.20eq), (E)-4,4,5,5-tetramethyl-2-(prop-1-en-1-yl)-1,3,2-dioxaborolane(20.7 g, 123 mmol, 1.00 equiv), XPhos Pd G3 (5.25 g, 6.20 mmol, 0.05 eq)and K₃PO₄ (52.6 g, 248 mmol, 2.00 eq) in THE (250 mL) and H₂O (100 mL)was degassed and purged with N₂ three times. The mixture was thenstirred at 60° C. for 2 h under N₂ atmosphere. The reaction mixture wascooled to ambient temperature and partitioned between water (300 mL) andEA (1.20 L). The organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by flash-column chromatography on silica gel (gradient elution,5% to 10% EA-petroleum ether) to give the title compound (25.0 g) as ayellow oil.

Step 2: 2-Methoxy-7-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

A solution of methyl (E)-6-methoxy-2-(prop-1-en-1-yl)nicotinate (25.0 g,120 mmol, 1.00 eq) in TfOH (100 mL) was stirred at 80° C. for 1 h. Thereaction mixture was then cooled to ambient temperature and and pouredinto saturated aqueous NaHCO₃ solution (1.00 L), then extracted with EA(1.00 L). The organic layer was washed with water (300 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by flash-column chromatography onsilica gel (gradient elution, 2% to 10% EA-petroleum ether) to give thetitle compound (20.8 g) as a white solid.

Steps 3-6: 2-Amino-7-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

The title compound was prepared from2-methoxy-7-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one using thetwo-step procedure described in Steps 4 and 5 for Intermediate 10,followed by the two-step procedure as described in Steps 4 and 5 in thepreparation of Intermediate 2. MS (ES+) C₉H₁₀N₂O₂ requires: 178, found:179[M+H]⁺. ¹H NMR, 400 MHz, DMSO-d6 δ 7.75 (d, J=8.8 Hz, 1H), 7.00 (s,2H), 6.40 (d, J=8.8 Hz, 1H), 4.70-4.45 (m, 2H), 2.90-2.70 (m, 2H), 1.37(d, J=5.6 Hz, 1H).

Intermediates 17 and 18:(7S,8R)-2-Amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(Intermediate 17) and(7R,8S)-2-amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(Intermediate 18)

each of which is represented by one of the structures shown below:

which is represented by one of the structures shown below:

which is represented by one of the structures shown below:

Step 1: Methyl (E)-2-(but-2-en-2-yl)-6-methoxynicotinate

K₃PO₄ (120 g, 565 mmol, 3.00 eq) and Pd(dppf)Cl₂—CH₂Cl₂ (7.70 g, 9.42mmol, 0.05 eq) were added to a solution of methyl2-chloro-6-methoxynicotinate (38.0 g, 188 mmol, 1.00 eq) and(Z)-2-(but-2-en-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (44.6 g,245 mmol, 1.30 eq) in THE (320 mL) and H₂O (80.0 mL). The reactionmixture was stirred under N₂ at 70° C. for 2 h. The reaction mixture wasdiluted with water (300 mL) and extracted with EA (250 mL×3). Theorganic layers were combined and dried over sodium sulfate, thenfiltered and concentrated in vacuo to give the residue. The residue waspurified by prep-HPLC (MeCN—H2O gradient with 0.1% TFA additive). Theproduct-containing fractions were adjusted to pH=8-9 with solid sodiumcarbonate and the mixture was extracted with EA (300 mL×3). The combinedorganic layers were washed with brine (500 mL), dried over Na₂SO₄,filtered and concentrated to give the title compound (37.0 g, 167 mmol,88.7% yield) as a yellow oil.

Steps 2 and 3:2-Hydroxy-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

The title compound was prepared from methyl(E)-2-(but-2-en-2-yl)-6-methoxynicotinate using the same procedure asdescribed in Step 2 of Intermediate 16, followed by the same procedureas described in Step 4 for Intermediate 10.

Step 4:rac-(7S,8S)-2-Hydroxy-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-oneandrac-(7S,8R)-2-hydroxy-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

DBU (60.8 mL, 403 mmol, 3.00 eq) was added to a solution of2-hydroxy-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (26.0g, 134 mmol, 1.00 eq) in toluene (290 mL). The reaction mixture wasstirred at 100° C. for 12 h, then was cooled to ambient temperature andconcentrated under vacuum. The residue was purified by flash-columnchromatography on silica gel (gradient elution, 1% to 10%methanol-dichloromethane) to afford the title compounds as a mixture ofisomers that were used in the next step without further purification.

Step 5:rac-(7S,8S)-2-Chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-oneandrac-(7S,8R)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

The title compounds were prepared fromrac-(7S,8S)-2-hydroxy-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-oneandrac-(7S,8R)-2-hydroxy-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-oneusing the same procedure as described in Step 5 of Intermediate 10. Thecis- and trans-racemic isomers were separated by prep-HPLC (column:Phenomenex luna C18 250*50 mm*10 um; mobile phase: [water(0.1%TFA)-MeCN]; B %: 35% MeCN-55% CAN over 20 min).rac-(7S,8S)-2-Chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-onewas the first compound to elute and was obtained as a white solid. MS(ES+) C₁₀H₁₃ClNO₂ requires: 211, found: 212[M+H]⁺. ¹H NMR: 400 MHz,CDCl₃ δ 8.29 (d, J=8.2 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H), 4.83 (dq, J=3.2,6.6 Hz, 1H), 3.09 (dq, J=3.2, 7.2 Hz, 1H), 1.49 (d, J=6.5 Hz, 3H), 1.30(d, J=7.2 Hz, 3H).rac-(7S,8R)-2-Chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-onewas the second compound to elute and was obtained as a white solid. MS(ES+) C₁₀H₁₀ClNO₂ requires: 211, found: 212[M+H]⁺. 1H NMR: 400 MHz,CDCl₃ δ 8.28 (d, J=8.2 Hz, 1H), 7.38 (d, J=8.2 Hz, 1H), 4.58-4.43 (m,1H), 3.05 (quin, J=7.2 Hz, 1H), 1.56-1.40 (m, 6H).

Step 6:(7S,8R)-2-Chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-oneand(7R,8S)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

rac-(7S,8R)-2-Chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-onewas separated by SFC (column: DAICEL CHIRALPAK AD (250 mm×50 mm, 10 um);mobile phase: MeOH in CO₂) to give the first eluting isomer (peak 1) asa white solid and second eluting isomer (peak 2) as a white solid.

Steps 7 and 8:(7S,8R)-2-Amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

The title compound (Intermediate 17) was prepared separately from thefirst eluting isomer using the same two-step procedure as described inSteps 4 and 5 for Intermediate 2. MS (ES+) C₁₀H₁₂N₂O₂ requires: 192,found: 193[M+H]⁺. ¹H NMR: 400 MHz, DMSO-d6 δ 7.77 (d, J=8.6 Hz, 1H),6.97 (s, 2H), 6.40 (d, J=8.6 Hz, 1H), 4.43-4.21 (m, 1H), 2.88-2.65 (m,1H), 1.35 (d, J=6.4 Hz, 3H), 1.25 (d, J=7.0 Hz, 3H). The absolutestereochemistry of Intermediate 17 was determined by X-ray crystalstructure.

Steps 9 and 10:(7R,8S)-2-amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

The title compound (Intermediate 18) was prepared separately from thesecond eluting isomer using the same two-step procedure as described inSteps 4 and 5 for Intermediate 2. MS (ES+) C₁₀H₁₂N₂O₂ requires: 192,found: 193[M+H]⁺. ¹H NMR: 400 MHz, DMSO-d6 δ 7.77 (d, J=8.6 Hz, 1H),6.97 (s, 2H), 6.40 (d, J=8.6 Hz, 1H), 4.43-4.21 (m, 1H), 2.88-2.65 (m,1H), 1.35 (d, J=6.4 Hz, 3H), 1.25 (d, J=7.0 Hz, 3H).

Intermediate 19:rac-(7S,8S)-2-Amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

Steps 1 and 2:rac-(7S,8S)-2-Amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

The title compound was prepared fromrac-(7S,8S)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(after step 5, Intermediate 17 and 18 synthesis) using the same two-stepprocedure as described in Steps 4 and 5 for Intermediate 2. MS (ES+)C₁₀H₁₂N₂O₂ requires: 192, found: 193[M+H]⁺. ¹H NMR: δ 7.75 (d, J=8.6 Hz,1H), 7.01 (s, 2H), 6.40 (d, J=8.6 Hz, 1H), 4.69 (d, J=6.6 Hz, 3.2 Hz,1H), 2.63-2.77 (m, 1H), 1.30 (d, J=6.6 Hz, 3H), 1.07 (d, J=7.2 Hz, 3H).

Intermediates 20 and 21:(R)-2-amino-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-oneand(S)-2-amino-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

each of which is represented by one of the structures shown below:

which is represented by one of the structures shown below:

Steps 1-5:2-((2,4-Dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

The title compound was prepared from methyl 2-chloro-6-methoxynicotinateand 4,4,5,5-tetramethyl-2-(3-methylbut-2-en-2-yl)-1,3,2-dioxaborolaneusing similar procedures as described above for Intermediate 17.

Step 6:(R)-2-((2,4-Dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-oneand(S)-2-((2,4-Dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

2-((2,4-Dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-onewas separated by SFC (column: DAICEL CHIRALPAK AS-H (250 mm*30 mm, 5um); mobile phase: [0.1% NH₄OH MeOH in CO₂]) to give one of (R orS)-2-((2,4-dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(1^(st) eluting isomer, 0.55 g, 79% yield) and the remaining one of (RorS)-2-((2,4-dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(2^(nd) eluting isomer, 0.55 g, 79% yield) as yellow oils.

Step 7 and 8:(R)-2-amino-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-oneand(S)-2-amino-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

The title compounds (Intermediates 20 and 21) were prepared separatelyfrom the 1^(st) and 2^(nd) eluting isomers, i.e.,(R)-2-((2,4-dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-oneand(S)-2-((2,4-Dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one,using the same procedure as described in Step 5 of Intermediate 2.Intermediate 20,(R)-2-Amino-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one,was obtained as a yellow solid. MS (ES+) C₁₁H₁₄N₂O₂ requires: 206,found: 207[M+H]⁺. ¹H-NMR (400 MHz, CD₃OD): δ ppm 7.89 (d, J=8.8 Hz, 1H),6.50 (d, J=8.8 Hz, 1H), 2.85-2.80 (m, 1H), 1.41 (s, 6H), 1.27 (d, J=7.2Hz, 3H). Intermediate 21,(S)-2-Amino-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one,was obtained as a yellow solid. MS (ES+) C₁₁H₁₄N₂O₂ requires: 206,found: 207[M+H]⁺. ¹H-NMR (400 MHz, CD₃OD): δ ppm 7.89 (d, J=8.8 Hz, 1H),6.50 (d, J=8.8 Hz, 1H), 2.85-2.80 (m, 1H), 1.41 (s, 6H), 1.27 (d, J=7.2Hz, 3H). The stereochemistry of Intermediate 20 was determined in thecontext of another compound using an X-ray crystal structure.

Intermediate 22: 5-Amino-3-isopropylpyrazine-2-carbonitrile

Step 1: 5-Amino-3-(prop-1-en-2-yl)pyrazine-2-carbonitrile

A mixture of 5-amino-3-chloropyrazine-2-carbonitrile (50.0 g, 324 mmol,1.00 eq), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane(81.54 g, 485.3 mmol, 1.50 eq), K₂CO₃ (89.42 g, 647.0 mmol, 2.00 eq),and Pd(PPh₃)₄ (18.69 g, 16.18 mmol, 0.05 eq) in dioxane (250 mL) and H₂O(50 mL) was stirred at 100° C. for 20 h under N₂. The reaction mixturewas then cooled to ambient temperature and diluted with EA (800 mL) andH₂O (300 mL). The biphasic mixture was then filtered through celite,then partitioned. The organic layer was washed with brine (500 mL×4),and then the organic layer was dried over Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by flash-columnchromatography on silica gel (gradient elution, 10% to 33% EA-petroleumether) to give the title compound (41.0 g, 39.0% yield) as a lightyellow solid.

Step 2: 5-Amino-3-isopropylpyrazine-2-carbonitrile

Pd/C (10 wt %, 10.0 g) was added to a solution of5-amino-3-(prop-1-en-2-yl)pyrazine-2-carbonitrile (45.0 g, 281 mmol,1.00 eq) in MeOH (800 mL). The suspension was degassed under vacuum andpurged with H₂ three times. The reaction mixture was stirred under H₂(15 psi) at 25° C. for 16 h. The mixture was filtered through celite andthe filtrate was concentrated under vacuum. The residue was treated withpetroleum ether/EA (110 mL, 10:1) and stirred at 25° C. for 10 min, thenfiltered. The filter cake was dried under vacuum to give the titlecompound (39.5 g, 85.6% yield) as a light yellow solid. MS (ES+) C₈H₁₀N₄requires: 162, found: 163[M+H]⁺. ¹H NMR: 400 MHz CDCl₃ δ: 7.83 (s, 1H),5.07 (br s, 2H), 3.43-3.33 (m, 1H), 1.28 (s, 3H), 1.26 (s, 3H).

Intermediate 23: 6-Amino-2-(2-fluoropropan-2-yl)nicotinonitrile

Step 1: 2-Bromo-6-(2-fluoropropan-2-yl)pyridine

DAST (10.3 g, 63.9 mmol, 3.00 equiv) was added to a solution of2-(6-bromopyridin-2-yl)propan-2-ol (4.60 g, 21.3 mmol, 1.00 equiv) indichloromethane (80 mL) at −78° C. under nitrogen atmosphere. Thereaction mixture was stirred for 1 h, and then water (20 mL) was added.The reaction mixture was further diluted with water (150 mL) andextracted with EA (150 mL×3). The combined organic layers were driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure to give the title compound (4.50 g, 97% yield) as a yellow oilwhich was used in the next step without further purification.

Step 2: N-(6-(2-Fluoropropan-2-yl)pyridin-2-yl)-1,1-diphenylmethanimine

A mixture of 2-bromo-6-(2-fluoropropan-2-yl)pyridine (3.99 g, 22.0 mmol,1.20 equiv), diphenylmethanimine (4.00 g, 18.3 mmol, 1.00 equiv),Pd₂(dba)₃ (1.68 g, 1.83 mmol, 0.10 equiv), XantPhos (2.12 g, 3.67 mmol,0.20 equiv) and cesium carbonate (17.9 g, 55.0 mmol, 3.00 equiv) indioxane (40 mL) was degassed and purged with nitrogen three times. Thereaction mixture was stirred at 100° C. for 1 hour under nitrogenatmosphere, then was filtered and concentrated under reduced pressure togive a residue. The residue was purified by flash-column chromatographyon silica gel (gradient elution, 0% to 25% EA-petroleum ether) to givethe title compound (5.00 g, 86% yield) as yellow oil.

Step 3: 6-(2-Fluoropropan-2-yl)pyridin-2-amine

HCl (4.0 M in dioxane, 10 mL) was added to a solution ofN-(6-(2-fluoropropan-2-yl)pyridin-2-yl)-1,1-diphenylmethanimine (5.30 g,16.7 mmol) in dioxane (20 mL) at 25° C. The reaction mixture was stirredat 25° C. for 1 h, then was treated with dropwise addition of saturatedsodium bicarbonate aqueous (20 mL). The crude mixture was diluted withwater (50 mL) and extracted with EA (60 mL×3). The combined organiclayers were dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by flash-column chromatography onsilica gel (gradient elution, 0% to 20% EA-petroleum ether) to give thetitle compound (1.20 g, 47% yield) as a yellow solid.

Step 4: 5-Bromo-6-(2-fluoropropan-2-yl)pyridin-2-amine

N-bromosuccinimide (1.25 g, 7.00 mmol, 0.900 equiv) was added to asolution of 6-(2-fluoropropan-2-yl)pyridin-2-amine (1.20 g, 7.78 mmol,1.00 equiv) in chloroform (30 mL). The reaction mixture was stirred at25° C. for 0.5 h, then sas diluted with water (30 mL) and extracted withEA (30 mL×3). The combined organic layers were dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure to givea residue. The residue was purified by flash-column chromatography onsilica gel (gradient elution, 0% to 25% EA-petroleum ether) to give thetitle compound (480 mg, 25% yield) as a yellow oil. ¹H NMR (400 MHz,CDCl₃): δ ppm 7.59 (d, J=8.4 Hz, 1H), 6.32 (d, J=8.4 Hz, 1H), 4.42 (s,2H), 1.81 (s, 3H), 1.76 (s, 3H).

Step 5: 6-Amino-2-(2-fluoropropan-2-yl)nicotinonitrile

A mixture of 5-bromo-6-(2-fluoropropan-2-yl)pyridin-2-amine (200 mg, 858μmol, 1.00 equiv), zinc cyanide (302 mg, 2.57 mmol, 3.00 equiv), DPPF(95.0 mg, 172 μmol, 0.200 equiv) and Pd₂(dba)₃ (79.0 mg, 85.8 μmol,0.100 equiv) in N,N-dimethylacetamide (2 mL) was degassed and purgedwith nitrogen three times. The reaction mixture was then stirred at 140°C. for 6 h under nitrogen. The reaction mixture was then diluted withwater (20 mL) and extracted with EA (20 mL×3). The combined organiclayers were dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified flash-column chromatography on silica gel (gradient elution, 0%to 25% EA-petroleum ether) to give the title compound (140 mg, 91%yield) as a brown solid. ¹H NMR (400 MHz, CDCl₃): δ ppm 7.68 (d, J=8.4Hz, 1H), 6.42 (d, J=8.8 Hz, 1H), 4.91 (s, 2H), 1.76 (s, 3H), 1.71 (s,3H).

Intermediate 24:(S)-5-Amino-3-(2-methylpyrrolidin-1-yl)pyrazine-2-carbonitrile

Step 1: (S)-5-Amino-3-(2-methylpyrrolidin-1-yl)pyrazine-2-carbonitrile

N,N-Diisopropylethylamine (0.237 mL, 1.36 mmol, 3.00 equiv) was added toa mixture of 5-amino-3-chloropyrazine-2-carbonitrile (70.0 mg, 453 umol,1.00 equiv) and (S)-2-methylpyrrolidine (HCl salt, 71.6 mg, 589 umol,1.30 equiv) in 2-methyl-2-butanol (2 mL). The reaction mixture wasstirred at 100° C. for 3 h, then was poured into 20 mL of water andextracted with EA (15 mL×3). The organic layers were dried by anhydroussodium sulfate, filtered and concentrated under reduced pressure to givethe title compound (90.0 mg, crude) as a yellow solid that was usedwithout further purification. MS (ES+) C₁₀H₁₃N₅ requires: 203, found:204[M+H]⁺.

Intermediate 25:(S)-5-Amino-3-(2-methylazetidin-1-yl)pyrazine-2-carbonitrile

Step 1: (S)-5-Amino-3-(2-methylazetidin-1-yl)pyrazine-2-carbonitrile

The title compound was prepared from5-amino-3-chloropyrazine-2-carbonitrile and (S)-2-methylazetidine CSAsalt using the same procedure as described in Step 1 of Intermediate 24.MS (ES+) C₉H₁₁N₅ requires: 189, found: 190[M+H]⁺.

Intermediate 26: 6-Amino-2-(1-fluoropropyl)nicotinonitrile

Step 1: 1-(6-Bromopyrazin-2-yl)propan-1-ol

n-BuLi (2.5 M, 6.73 mL, 16.8 mmol, 2.00 equiv) was added dropwise to amixture of 2,6-dibromopyrazine (2.00 g, 8.41 mmol, 1.00 equiv) indichloromethane (20 mL) at −70° C., then propionaldehyde (1.60 g, 27.5mmol, 3.27 equiv) in dichloromethane (3 mL) was added into the mixtureat −70° C. The reaction mixture was stirred at −70° C. for 1 h undernitrogen, and then saturated aqueous ammonium chloride solution (60 mL)was added. The reaction mixture was extracted with EA (60 mL×3), and theorganic layers were combined. The combined organic layers were driedover anhydrous sodium sulfate, filtered, and concentrated to give aresidue. The residue was purified by flash-column chromatography onsilica gel (gradient elution, 5% to 10% EA-petroleum ether) to give thetitle compound (1.40 g, 74% yield) as yellow oil.

Steps 2-6: 5-Amino-3-(1-fluoropropyl)pyrazine-2-carbonitrile

The title compound was prepared from 1-(6-bromopyrazin-2-yl)propan-1-olusing the same five-step procedure as described in Steps 1-5 ofIntermediate 23. ¹H-NMR (400 MHz, CD₃OD): δ ppm 7.98 (s, 1H), 5.67-5.50(m, 1H), 5.34 (s, 2H), 2.18-1.90 (m, 2H), 1.07 (t, J=7.2 Hz, 3H).

Intermediate 27:2′-Aminospiro[cyclopropane-1,7′-pyrano[4,3-b]pyridin]-5′(8′H)-one

Steps 1-5:2′-Aminospiro[cyclopropane-1,7′-pyrano[4,3-b]pyridin]-5′(8′1)-one

The title compound was prepared from 4-oxaspiro[2.5]octan-7-one usingthe same five-step procedure described in Steps 1-5 for Intermediate 2.MS (ES+) C₁₀H₁₀N₂O₂ requires: 190, found: 191 [M+H]⁺.

Intermediate 28:5-Amino-3-(1,1,1-trifluoropropan-2-yl)pyrazine-2-carbonitrile Compound63

Step 1: 5-Amino-3-(3,3,3-trifluoroprop-1-en-2-yl)pyrazine-2-carbonitrile

Pd(PPh₄)₃ (657 mg, 776 umol, 0.200 equiv) and potassium carbonate (1.07g, 7.76 mmol, 2.00 equiv) were added to a solution of5-amino-3-chloropyrazine-2-carbonitrile (600 mg, 3.88 mmol, 1.00 equiv)and4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborinane(1.03 g, 4.66 mmol, 1.20 equiv) in dioxane (5 mL) and water (0.5 mL).The mixture was stirred at 80° C. for 16 h under nitrogen. The reactionmixture was then cooled to ambient temperature, filtered, andconcentrated under reduced pressure to give a residue. The residue waspurified by prep-HPLC (column: Phenomenex Synergi Max-RP 250*50 mm*10um; mobile phase: [water(0.1% TFA)-MeCN]; B %: 22MeCN %-52MeCN %) togive the title compound (200 mg, 24% yield) as white solid.

Step 2: 5-Amino-3-(1,1,1-trifluoropropan-2-yl)pyrazine-2-carbonitrile

Chlororhodium triphenylphosphine (432 mg, 467 umol, 0.50 equiv) wasadded to a solution of5-amino-3-(3,3,3-trifluoroprop-1-en-2-yl)pyrazine-2-carbonitrile (200mg, 934 umol, 1.00 equiv) in ethanol (10 mL). The reaction mixture wasstirred at 50° C. for 16 h under H₂ (15 psi), then was filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by prep-HPLC (column: Phenomenex luna C18 250*50 mm*10 um;mobile phase: [water(0.1% TFA)-MeCN]; B %: 32%-62%) to give the titlecompound (20 mg, 9.9% yield) as white solid. ¹H-NMR (400 MHz, CD₃OD): δppm 7.90 (s, 1H), 3.99-3.90 (m, 1H), 1.54 (d, J=6.8, 3H).

Intermediates 29 and 30:(S)-5-Amino-3-(sec-butyl)pyrazine-2-carbonitrile and(R)-5-amino-3-(sec-butyl)pyrazine-2-carbonitrile

each of which is represented by one of the structures shown below:

Steps 1 and 2: 5-Amino-3-(sec-butyl)pyrazine-2-carbonitrile

The title compound was prepared using the same procedure as described inSteps 1 and 2 of Intermediate 22.

Step 3: (S)-5-Amino-3-(sec-butyl)pyrazine-2-carbonitrile and(R)-5-amino-3-(sec-butyl)pyrazine-2-carbonitrile

5-Amino-3-(sec-butyl)pyrazine-2-carbonitrile (320 mg, 1.82 mmol) wasseparated by SFC (column: DAICEL CHIRALPAK AD-H (250 mm*30 mm, 5 um);mobile phase: EtOH with 0.1% NH₄OH gradient in CO₂) to give one of (R orS)-5-Amino-3-(sec-butyl)pyrazine-2-carbonitrile (1^(st) eluting isomer,95 mg, 30% yield) as an off-white solid and the remaining one of (R orS)-5-Amino-3-(sec-butyl)pyrazine-2-carbonitrile (2^(nd) eluting isomer,128 mg, 39.7% yield) as a white solid. Peak 1: MS (ES+) C₉H₁₂N₄requires: 176, found: 177[M+H]⁺. ¹H-NMR (400 MHz, CDCl₃) δ=7.83 (s, 1H),5.07 (br s, 2H), 3.23-3.03 (m, 1H), 1.81-1.62 (m, 2H), 1.25 (d, J=6.8Hz, 3H), 0.87 (t, J=7.6 Hz, 3H). Peak 2: MS (ES+) C₉H₁₂N₄ requires: 176,found: 177[M+H]⁺. ¹H-NMR (400 MHz, CDCl₃) δ=7.83 (s, 1H), 5.08 (br s,2H), 3.20-3.02 (m, 1H), 1.85-1.64 (m, 2H), 1.25 (d, J=6.8 Hz, 3H), 0.87(t, J=7.6 Hz, 3H).

II. Synthesis of Arylchloride Intermediates

Intermediate 31: 2-(6-Chloro-1-methoxy-2,7-naphthyridin-4-yl)propan-2-ol

Step 1: 4-Bromo-6-chloro-2,7-naphthyridin-1(2H)-one

NBS (70.9 g, 398 mmol, 1.20 eq) was added to a solution of6-chloro-2,7-naphthyridin-1(2H)-one (60.0 g, 332 mmol, 1.00 eq) in DMF(600 mL). The reaction mixture was stirred at 20° C. for 2 h, then waspoured into water (1 L) and filtered. The filter cake was dried undervacuum to give compound 2 (90.8 g, crude) as a brown solid. MS (ES+)C₈H₄BrClN₂O requires: 260, found: 261 [M+H]⁺.

Step 2: 4-Bromo-1,6-dichloro-2,7-naphthyridine

4-Bromo-6-chloro-2,7-naphthyridin-1(2H)-one (70.8 g, 272 mmol, 1.00 eq)was added in portions to POCl₃ (484 g, 3.16 mol, 293 mL, 11.5 eq) at 25°C. The reaction mixture was then stirred at 110° C. for 3 h. Thereaction mixture was then concentrated under vacuum, and the residue wasadjusted to pH=8 with saturated aqueous Na₂CO₃ at 25° C. The mixture wasextracted with DCM (500 mL×3), washed with brine (500 mL), dried overNa₂SO₄, filtered and concentrated under vacuum to give the titlecompound (75.0 g, 269 mmol, 98.9% yield) as a yellow solid. MS (ES+)CSH₃BrCl₂N₂ requires: 278, found: 279[M+H]⁺.

Step 3: 4-Bromo-6-chloro-1-methoxy-2,7-naphthyridine

A suspension of 4-bromo-1,6-dichloro-2,7-naphthyridine (75.0 g, 269mmol, 1.00 eq), K₂CO₃ (111 g, 809 mmol, 3.00 eq) in MeOH (3 L) wasstirred at 25° C. for 16 h. The reaction mixture was then concentratedunder vacuum, and the residue was dissolved in H₂O (300 mL) andextracted with DCM (100 mL×2). The combined organic layers wereconcentrated under vacuum to give a residue. The residue was trituratedin petroleum ether/EA (40 mL 20:1) and filtered. The filter cake wasdried under vacuum to give the title compound (47.0 g, 171 mmol, 63.6%yield) as a yellow solid.

Step 4: 6-Chloro-4-(1-ethoxyvinyl)-1-methoxy-2,7-naphthyridine

A solution of 4-bromo-6-chloro-1-methoxy-2,7-naphthyridine (47.0 g, 171mmol, 1.00 eq), tributyl(1-ethoxyvinyl)stannane (74.4 g, 206 mmol, 69.6mL, 1.20 eq) and Pd(PPh₃)₄ (19.8 g, 17.1 mmol, 0.10 eq) in toluene (500mL) was stirred at 80° C. for 16 h under N₂. The reaction mixture wasthen cooled to 20° C. and poured into saturated aqueous KF solution (500mL) and stirred for 1 h. The aqueous mixture was extracted with EA (300mL×3), and the organic layers were combined. The combined organic layerwas concentrated under vacuum to give the title compound (64.0 g, crude)as a yellow oil. MS (ES+) C₁₃H₁₃ClN₂O₂ requires: 264, found: 265 [M+H]⁺.

Step 5: 1-(6-Chloro-1-methoxy-2,7-naphthyridin-4-yl)ethan-1-one

Aqueous HCl (1.50 M, 20.1 mL, 0.10 eq) was added to a solution of6-chloro-4-(1-ethoxyvinyl)-1-methoxy-2,7-naphthyridine (80.0 g, 302mmol, 1.00 eq) in THE (480 mL) and H₂O (80 mL). The reaction mixture wasstirred at 25° C. for 1 h. The reaction mixture was then poured intosaturated aqueous NaHCO₃ solution (500 mL) and extracted with EA (300mL×2). The organic layers were combined and concentrated under vacuum.The residue was purified by flash-column chromatography on silica gel(gradient elution, 5% to 50% EA-petroleum ether) to give the titlecompound (28.0 g, 118 mmol, 39.1% yield) as a white solid. MS (ES+)C₁₁H₉ClN₂O₂ requires: 236, found: 237[M+H]⁺.

Step 6: 2-(6-Chloro-1-methoxy-2,7-naphthyridin-4-yl)propan-2-ol

MeMgBr (3.0 M in diethyl ether, 118 mL, 3.00 eq) was added to a solutionof 1-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)ethan-1-one (28.0 g, 118mmol, 1.00 eq) in THE (300 mL) at 0˜10° C. The mixture was stirred at0˜10° C. for 2 h, and then was poured into saturated aqueous NH₄Clsolution (300 mL) and extracted with EA (200 mL×2). The organic layerswere combined and concentrated under vacuum to give the title compound(33 g, crude) as a yellow oil. MS (ES+) C₁₂H₁₃ClN₂O₂ requires: 252,found: 253[M+H]⁺.

Intermediate 31a

4-(2-azidopropan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine can beobtained from 2-(6-Chloro-1-methoxy-2,7-naphthyridin-4-yl)propan-2-olupon treatment with TMSN₃, InBr₃ and DCM.

Intermediate 32: 4-bromo-7-chloro-1-iodo-2,6-naphthyridine

Step 1: 5-bromo-N-tert-butyl-2-chloroisonicotinamide

2-methylpropan-2-amine (1.47 g, 20.2 mmol), EDC HCl (4.85 g, 25.3 mmol)and HOBT (3.41 g, 25.3 mmol) were added to a solution of5-bromo-2-chloropyridine-4-carboxylic acid (4 g, 16.9 mmol) in DMF (30mL) under an atmosphere of nitrogen and the reaction mixture was stirredovernight at rt. The resulting solution was added water and suspensionwas extracted with EA, and then the organic layers were combined, driedover anhydrous sodium sulfate and concentrated under vacuum. The residuewas purified by flash-column chromatography-column chromatography togive 3 g (60.9%) of the title compound as a white solid. MS (ES+)C₁₀H₁₂BrClN₂O requires 290, found 291 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆)δ 8.64 (s, 1H), 8.30 (s, 1H), 7.58 (s, 1H), 1.36 (s, 9H).

Step 2: (E)-N-tert-butyl-2-chloro-5-(2-ethoxyvinyl)isonicotinamide

2-[(E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.49 g,7.53 mmol), Cs₂CO₃ (4.46 g, 13.7 mmol) and Pd(dppf)Cl₂ (501 mg, 685μmol) were added to a solution of5-bromo-N-tert-butyl-2-chloropyridine-4-carboxamide (2 g, 6.85 mmol) indioxane (30 mL) and H₂O (6 mL) under an atmosphere of nitrogen and thereaction mixture was stirred for 2 h at 80° C. The resulting solutionwas diluted with water and extracted with EA, and then the organiclayers combined, dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was purified by flash-column chromatography togive 1.2 g (62.1%) of the title compound as a yellow solid. MS (ES+)C₁₄H₁₉ClN₂O₂ requires 282, found 283 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ8.55 (s, 1H), 8.20 (s, 1H), 7.35 (d, 114, J=13.0 Hz), 7.28 (s, 1H), 5.79(d, 114, J=13.0 Hz), 3.90 (q, 211, J=7.0 Hz), 1.35 (s, 9H), 1.26 (t,311, J=7.0 Hz).

Step 3: 7-chloro-2,6-naphthyridin-1(2H)-one

TFA (20 mL) was added toN-tert-butyl-2-chloro-5-[(E)-2-ethoxyethenyl]pyridine-4-carboxamide (1.2g, 4.24 mmol) and the reaction mixture was stirred overnight at 100° C.The resulting mixture was concentrated under vacuum to give 600 mg(91.5%) of the title compound as a red solid. The crude product was useddirectly for next step without any further purification. MS (ES+)C₈H₅ClN₂O requires 180, found 181 [M+H]⁺.

Step 4: 4-bromo-7-chloro-2,6-naphthyridin-1(2H)-one

NBS (3.54 g, 19.9 mmol) was added to a solution of7-chloro-1,2-dihydro-2,6-naphthyridin-1-one (3 g, 16.6 mmol) in DCM (40mL) and the reaction mixture was stirred for 1 h at rt. The solid wascollected by filtration to give 3 g (69.7%) of the title compound as awhite solid. MS (ES+) C₈H₄BrClN₂O requires 258, found 259 [M+H]⁺. ¹H NMR(300 MHz, DMSO-d₆) δ 12.09 (s, 1H), 8.93 (s, 1H), 8.04 (s, 1H), 7.70 (d,114, J=6.0 Hz).

Step 5: 4-bromo-7-chloro-2,6-naphthyridin-1-yl trifluoromethanesulfonate

Tf₂O (4.34 g, 15.4 mmol) was added drop wise over 10 min to a solutionof 4-bromo-7-chloro-1,2-dihydro-2,6-naphthyridin-1-one (1 g, 3.85 mmol)in DCM (15 mL) and TEA (777 mg, 7.70 mmol) at −78° C. and the resultingsolution was stirred for 0.5 h at −78° C. The mixture was warmed to roomtemperature and stirred at this temperature for another 0.5 h. Thereaction was then quenched by the addition of 2 mL of water/ice,extracted with DCM, and then the organic layers combined, dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waspurified using flash-column chromatography to give 1 g (66.6%) of thetitle compound as a white solid. MS (ES+) C₉H₃BrClF₃N₂O₃S requires 390,found 391 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 9.47 (s, 1H), 8.78 (s,1H), 8.14 (d, 1H, J=0.9 Hz).

Step 6: 4-bromo-7-chloro-1-iodo-2,6-naphthyridine

NaI (952 mg, 6.35 mmol) was added to a solution of4-bromo-7-chloro-2,6-naphthyridin-1-yl trifluoromethanesulfonate (500mg, 1.27 mmol) in MCCN (9 mL) and the resulting mixture was cooled to 0°C. followed by addition of trifluoromethanesulfonic acid (381 mg, 2.54mmol) in MCCN (1 mL) drop wise over 10 min. The mixture was then stirredat rt for 1.5 h. The resulting solution was extracted with EA, and thenthe organic layers combined, washed with brine, dried over anhydroussodium sulfate and concentrated under vacuum to give 500 mg of titlecompound as a black solid which was used directly for next withoutfurther purification. MS (ES+) C₉H₃BrClF₃N₂O₃S requires 368, found 369[M+H]⁺.

Intermediates 33 and 34:(R)-2-(6-Chloro-1-cyclopropoxy-2,7-naphthyridin-4-yl)butan-2-amine and(S)-2-(6-chloro-1-cyclopropoxy-2,7-naphthyridin-4-yl)butan-2-amine

Each of which is represented by one of the structures below:

Step 1: 4-Bromo-6-chloro-1-cyclopropoxy-2,7-naphthyridine

To a solution of cyclopropanol (5.75 g, 98.9 mmol) in THE (250 mL) wasadded sodium hydride (4.32 g, 108 mmol, 60% purity) at 0° C. Thereaction mixture was stirred at 0° C. for 20 min, and then4-bromo-1,6-dichloro-2,7-naphthyridine (25.0 g, 90.0 mmol) was added toreaction mixture. The reaction mixture was warmed to 25° C. for 40 min,then was poured into water (1 L) and extracted with ethyl acetate (500mL×3). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to give aresidue. The crude product was purified by tritaration in petroleumether/EA (240 mL/20 mL) at 25° C. to give the title compound (45.0 g,84% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ ppm 9.27 (s,1H), 8.40 (s, 1H), 7.88 (s, 1H), 4.57-4.50 (m, 1H), 0.95-0.92 (m, 4H).

Steps 2-3: 1-(6-Chloro-1-cyclopropoxy-2,7-naphthyridin-4-yl)ethan-1-one

The title compound was prepared from4-bromo-6-chloro-1-cyclopropoxy-2,7-naphthyridine using the sametwo-step sequence as described in Steps 4 and 5 of Intermediate 31.

Step 4: 2-(6-Chloro-1-cyclopropoxy-2,7-naphthyridin-4-yl)butan-2-ol

To a solution of1-(6-chloro-1-cyclopropoxy-2,7-naphthyridin-4-yl)ethan-1-one (27.0 g,103 mmol) in MTBE (540 mL) was added ethylmagnesium bromide (3.0 M, 103mL) at 0° C. under nitrogen atmosphere. The reaction mixture was stirredat 0° C. for 15 min, then was quenched by addition water (1000 mL) andextracted with EA (800 mL×3). The combined organic layers were driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure to give the title compound (34 g, crude) as a yellow oil whichwas used in the next step directly.

Step 5:(R)-2-(6-Chloro-1-cyclopropoxy-2,7-naphthyridin-4-yl)butan-2-amine or(S)-2-(6-chloro-1-cyclopropoxy-2,7-naphthyridin-4-yl)butan-2-amine

To a solution of2-(6-chloro-1-cyclopropoxy-2,7-naphthyridin-4-yl)butan-2-ol (34.0 g, 116mmol) in dichloromethane (340 mL) was added trimethylsilyl azide (35.0g, 304 mmol, 40 mL) and boron trifluoride diethyl etherate (34.5 g, 243mmol, 30 mL) under nitrogen atmosphere. The reaction mixture was stirredat 25° C. for 2 h, then was diluted with water (1000 mL) and extractedwith DCM (800 mL×3). The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to give a residue. The residue was purified by silica gelcolumn chromatography (petroleum ether:ethyl acetate=1:0 to 3:1) to giverac-2-(6-chloro-1-cyclopropoxy-2,7-naphthyridin-4-yl)butan-2-amine (15.0g, 45% yield for two steps) as a yellow solid. This racemic compound wasseparated by SFC (column: Phenomenex-Cellulose-2 (250 mm×30 mm, 10 um);mobile phase: [0.1% MeOH (with 0.1% NH₄OH) in CO₂] to give(R)-2-(6-chloro-1-cyclopropoxy-2,7-naphthyridin-4-yl)butan-2-amine or(S)-2-(6-chloro-1-cyclopropoxy-2,7-naphthyridin-4-yl)butan-2-amine(Intermediate 33, first eluting isomer, 2.90 g, 19% yield) as a yellowsolid and a second eluting isomer (Intermediate 34, 4.80 g, 32% yield)as a white solid. Intermediate 33: ¹H NMR (400 MHz, CDCl₃): δ ppm 9.36(s, 1H), 8.36 (s, 1H), 8.23 (s, 1H), 4.58-4.51 (m, 1H), 2.10-2.04 (m,2H), 1.84 (s, 3H), 0.96-0.92 (m, 4H), 0.87 (t, J=7.2 Hz, 3H).

Intermediate 35:4-(2-azidopropan-2-yl)-6-chloro-1-cyclopropoxy-2,7-naphthyridine

Intermediate 35 was made using a similar procedure as described forIntermediates 33 and 34, except in step 4, methylmagnesium Grignard wasused and no chiral separation was needed.

Intermediates 36a-36o

Intermediates were made using a similar procedure as described forIntermediate 35, except that a different reagent was used as noted belowin Step 1.

Inter- Reagent used in medi- Step 1 of prep for ates StructureIntermediate 35 36a

EtOH 36b

iPrOH 36c

cyclobutanol 36d

36e

36f

36g

36h

36i

36j

36k

36l

36m

36n

36o

Intermediate 37 and 38:(R)-4-(2-Azidobutan-2-yl)-6-chloro-1-(1-methylcyclopropoxy)-2,7-naphthyridineand(S)-4-(2-azidobutan-2-yl)-6-chloro-1-(1-methylcyclopropoxy)-2,7-naphthyridine

Intermediates 37 and 38 were made using a similar procedure as describedfor Intermediates 33 and 34, except in step 1, 1-methylcyclopropane-1-olwas used. The racemic title compound was separated by SFC (column:Daicel Chiralpak AD-H (250 mm×30 mm, 5 um); mobile phase: [IPA (with0.1% NH₄OH) in CO₂]) to give(R)-4-(2-azidobutan-2-yl)-6-chloro-1-(1-methylcyclopropoxy)-2,7-naphthyridineor(S)-4-(2-azidobutan-2-yl)-6-chloro-1-(1-methylcyclopropoxy)-2,7-naphthyridine(Intermediate 37, first eluting isomer, 200 mg, 29% yield) as a whiteoil and a second eluting isomer (Intermediate 38, 290 mg, 42% yield) asa white oil. Intermediate 37 and 38: MS (ES+) C₁₆H₁₈ClN₅O requires 331,found 332 [M+H]⁺.

Intermediate 39 and 40:(R)-4-(1-Azido-1-cyclopropylethyl)-6-chloro-1-(1-methylcyclopropoxy)-2,7-naphthyridineand(S)-4-(1-azido-1-cyclopropylethyl)-6-chloro-1-(1-methylcyclopropoxy)-2,7-naphthyridine

Intermediates 39 and 40 were made using a similar procedure as describedfor Intermediates 33 and 34, except in step 4, cyclopropylmagnesiumbromide was used and the reaction was stirred at 60° C. for 30 min. Theracemic title compound was separated by SFC(column: Daicel ChiralpakAD-H (250 mm×30 mm, 5 um); mobile phase: [IPA (with 0.1% NH₄OH) in CO₂])to give:(R)-4-(1-Azido-1-cyclopropylethyl)-6-chloro-1-(1-methylcyclopropoxy)-2,7-naphthyridineor(S)-4-(1-azido-1-cyclopropylethyl)-6-chloro-1-(1-methylcyclopropoxy)-2,7-naphthyridine(Intermediate 39, first eluting isomer, 130 mg, 28% yield) as a yellowsolid and a second eluting isomer (Intermediate 40, 150 mg, 32% yield)as a yellow solid.

Intermediates 41 and 42:(7R,8R)-2-Amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-oneand(7S,8S)-2-amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

each of which is represented by one of the structures shown below:

which is represented by one of the structures shown below:

which is represented by one of the structures shown below:

Step 1:(7R,8R)-2-Chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-oneand(7S,8S)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

rac-(7R,8R)-2-Chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(6.0 g, 28.3 mmol) was separated by SFC (Daicel Chiralpak AD, MeOHgradient in CO₂ with 0.1% NH₄OH) to give two peaks separately. The firsteluting isomer (3 g, 50% yield) and second eluting isomer (2.8 g, 46%yield) were obtained as yellow solids.

Steps 2 and 3: One of (7R,8R)- or(7S,8S)-2-Amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

The title compound (Intermediate 41) was prepared from one of (7R,8R)-or(7S,8S)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(first eluting isomer from step 1) using the same two-step procedure asdescribed in Steps 4 and 5 for Intermediate 2. ¹H-NMR (400 MHz,6d-DMSO): δ ppm 7.76 (d, J=8.8 Hz, 1H), 7.02 (s, 2H), 6.41 (d, J=8.8 Hz,1H), 4.70 (d, J=3.2, 6.4 Hz, 1H), 2.77-2.66 (m, 1H), 1.31 (d, J=6.8 Hz,3H), 1.08 (d, J=7.2 Hz, 3H). MS (ES+) C₁₀H₁₂N₂O₂ requires: 192, found:193[M+H]⁺.

Steps 4 and 5: The remaining one of (7R,8R)- or(7S,8S)-2-Amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

The title compound (Intermediate 42) was prepared from the remaining oneof (7R,8R)- or(7S,8S)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(second eluting isomer from step 1) using the same two-step procedure asdescribed in Steps 4 and 5 for Intermediate 2. MS (ES+) C₁₀H₁₂N₂O₂requires: 192, found: 193[M+H]⁺.

Intermediate 43 and 44:(R)-4-(1-Azido-1-cyclopropylethyl)-6-chloro-1-methoxy-2,7-naphthyridineor(S)-4-(1-azido-1-cyclopropylethyl)-6-chloro-1-methoxy-2,7-naphthyridine

Intermediates 43 and 44 were made using a similar procedure as describedfor Intermediates 33 and 34, except in step 1, methanol was used and instep 4, cyclopropylmagnesium bromide was used and the reaction wasstirred at 60° C. for 30 min. The racemic title compound (1.20 g, 3.95mmol) was separated by SFC (column: Daicel Chiralpak IG (250 mm×30 mm,10 um); mobile phase: [MeOH (with 0.1% NH₄OH) in CO₂]) to give:(R)-4-(1-azido-1-cyclopropylethyl)-6-chloro-1-methoxy-2,7-naphthyridineor(S)-4-(1-azido-1-cyclopropylethyl)-6-chloro-1-methoxy-2,7-naphthyridine(Intermediate 43, first eluting isomer, 490 mg, 40% yield) as a yellowoil and a second eluting isomer (Intermediate 44, 430 mg, 34% yield) asa yellow oil.

Intermediate 45:2′-Amino-5′H,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridin]-5′-one

Step 1: Methyl 2-(3-bromo-6-chloropyridin-2-yl)acetate

LiHMDS (1 M, 388 mL) was added to a solution of3-bromo-6-chloro-2-methylpyridine (20.0 g, 96.9 mmol) in THE (300 mL) at25° C. under nitrogen. After 2.5 h, dimethyl carbonate (14.0 g, 155mmol) was added to the mixture and stirred at 25° C. for 13.5 h. Thereaction mixture was then was added to saturated aqueous NH₄Cl (1000 mL)and extracted with EA (60 mL×3). The combined organic layers were driedover anhydrous sodium sulfate, filtered and concentrated to give aresidue. The residue was purified by flash-column chromatography onsilica gel (gradient elution, 0% to 10% EA-petroleum ether) to give thetitle compound (18.0 g, 70% yield) as a yellow oil. ¹H NMR (400 MHz,CDCl₃): δ ppm 7.81 (d, J=8.4 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 4.03 9s,2H), 3.74 (s, 3H).

Step 2: Methyl1-(3-bromo-6-chloropyridin-2-yl)cyclopropane-1-carboxylate

Tetrabutylammonium bromide (2.44 g, 7.56 mmol) and NaOH (50 mL, 50 wt %in water) were added to a solution of 1,2-dibromoethane (10.7 g, 56.7mmol) and methyl 2-(3-bromo-6-chloropyridin-2-yl)acetate (10.0 g, 37.8mmol) in toluene (50 mL) at 25° C. The reaction mixture was stirred at25° C. for 16 h, then was diluted with water (300 mL) and extracted withEA (200 mL×3). The combined organic layers were dried over anhydroussodium sulfate, filtered and concentrated to give a residue. The residuewas purified by flash-column chromatography on silica gel (gradientelution, 0% to 10% EA-petroleum ether) to give the title compound (6.10g, 56% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ ppm 7.81 (d,J=8.4 Hz, 1H), 7.15 (d, J=8.0 Hz, 1H), 3.66 (s, 3H), 1.81-1.75 (m, 2H),1.46-1.41 (m, 2H).

Step 3: (1-(3-Bromo-6-chloropyridin-2-yl)cyclopropyl)methanol

Diisobutylaluminium hydride (1 M, 56 mL) was added to a solution ofmethyl 1-(3-bromo-6-chloropyridin-2-yl)cyclopropane-1-carboxylate (5.40g, 18.6 mmol) in DCM (80 mL) at −78° C. under nitrogen. The reactionmixture was stirred at −78° C. for 0.5 h, then was quenched by additionof aqueous saturated NH₄Cl solution (50 mL), diluted with water (200 mL)and extracted with EA (200 mL×3). The combined organic layers were driedover anhydrous sodium sulfate, filtered and concentrated to give thecrude title compound (5.00 g, crude) as a yellow solid which was used inthe next step without further purification.

Step 4: Methyl5′-oxo-5′H,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridine]-2′-carboxylate

Triethylamine (2.31 g, 22.9 mmol) and Pd(dppf)Cl₂ (557 mg, 762 μmol)were added to a solution of(1-(3-Bromo-6-chloropyridin-2-yl)cyclopropyl)methanol in MeOH (25 mL)and DMF (25 mL) under nitrogen atmosphere. The suspension was degassedunder vacuum and purged with carbon monoxide several times. The mixturewas stirred under carbon monoxide (50 psi) at 80° C. for 16 h. Thereaction mixture was then concentrated to remove methanol, diluted withwater (100 mL) and extracted with EA (60 mL×3). The combined organiclayers were washed with brine (100 mL×3), dried over anhydrous sodiumsulfate, filtered and concentrated to give a residue. The title compound(1.8 g, crude) was obtained as a yellow solid and used in the next stepwithout further purification. MS (ES+) C₁₀H₁₀N₂O₂ requires: 233, found:234[M+H]⁺.

Step 5:5′-Oxo-5′H,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridine]-2′-carboxylicacid

Lithium hydroxide (555 mg, 23.2 mmol) was added to a solution of methyl5′-oxo-5′H,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridine]-2′-carboxylate(1.80 g, 7.72 mmol) in methanol (30 mL) and water (10 mL). The reactionmixture was stirred at 25° C. for 0.5 h, then was concentrated to removethe methanol. The mixture was diluted with water (60 mL) and extractedwith EA (50 mL×3). The aqueous layer was acidified by addition aqueoushydrochloric acid solution (6 M, 5 mL), then the mixture was extractedwith EA (50 mL×3). The combined organic layers were dried over anhydroussodium sulfate, filtered and concentrated to give the title compound(1.20 g, 71% yield) as a brown solid that was used without furtherpurification.

Step 6: tert-Butyl(5′-oxo-5′H,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridin]-2′-yl)carbamate

Triethylamine (831 mg, 8.21 mmol) and diphenyl phosphoryl azide (2.26 g,8.21 mmol) were added to a solution of5′-oxo-5′H,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridine]-2′-carboxylicacid (1.20 g, 5.47 mmol) in tert-butanol (20 mL). The reaction mixturewas stirred at 100° C. for 1 h, then was cooled to ambient temperature,diluted with water (60 mL), and extracted with EA (50 mL×3). Thecombined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated to give a residue. The residue was purified byflash-column chromatography on silica gel (gradient elution, 0% to 50%EA-petroleum ether) to give the title compound (330 mg, 19% yield) as ayellow solid and2′-amino-5′H,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridin]-5′-one(420 mg, 28% yield) as a yellow oil.

Step 7:2′-Amino-5′H,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridin]-5′-one

HCl in dioxane (4.0 M, 0.5 mL) was added to a solution of tert-butyl(5′-oxo-5′H,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridin]-2′-yl)carbamate(100 mg, 344 μmol) in dioxane (1.5 mL) at 25° C. The reaction mixturewas stirred for 10 min, then was concentrated. DCM (2 mL) and TFA (1 mL,13.5 mmol) were added to the residue, and the reaction mixture wasstirred at 25° C. for 30 min. The reaction mixture was then concentratedand EA (5 mL) was added to the residue. The mixture was neutralized byaddition of saturated aqueous NaHCO₃ (20 mL) and extracted with EA (15mL×3). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated under to give the title compound(60.0 mg, 92% yield) as a yellow oil that was used in the next stepwithout further purification. MS (ES+) C₁₂H₁₁NO₄ requires: 190, found:191 [M+H]⁺.

Intermediates 46 and 47:(S)-2-Amino-7-ethyl-7-methylfuro[3,4-b]pyridin-5(7H)-one and(R)-2-amino-7-ethyl-7-methylfuro[3,4-b]pyridin-5(7H)-one

each of which is represented by one of the structures shown below:

which is represented by one of the structures shown below:

which is represented by one of the structures shown below:

Steps 1-4: 2-Chloro-7-ethyl-7-methylfuro[3,4-b]pyridin-5(7H)-one

The title compound was prepared from methyl 2-chloro-6-methoxynicotinateand 2-(but-1-en-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane usingsimilar procedures as described above for Intermediate 17 (Steps 1-3,5), except CsF was used as a base in Step 1 and Step 2 was conducted at25° C. for 1 h.

Step 5: (S)-2-Chloro-7-ethyl-7-methylfuro[3,4-b]pyridin-5(7H)-one and(R)-2-chloro-7-ethyl-7-methylfuro[3,4-b]pyridin-5(7H)-one

2-Chloro-7-ethyl-7-methylfuro[3,4-b]pyridin-5(7H)-one (1.9 g, 8.98 mmol)was separated by SFC (column: DAICEL CHIRALPAK AS-H (250 mm*30 mm, 5um); mobile phase: [0.1% NH₄OH EtOH in CO₂]) to give one of (R orS)-2-chloro-7-ethyl-7-methylfuro[3,4-b]pyridin-5(7H)-one (1a elutingisomer, 0.70 g, 37% yield) and the remaining one of (R orS)-2-Chloro-7-ethyl-7-methylfuro[3,4-b]pyridin-5(7H)-one (2^(nd) elutingisomer, 0.90 g, 47% yield) as yellow oils.

Steps 6 and 7: One of (R orS)-2-amino-7-ethyl-7-methylfuro[3,4-b]pyridin-5(7H)-one

The title compound (Intermediate 46) was prepared from one of (R orS)-2-chloro-7-ethyl-7-methylfuro[3,4-b]pyridin-5(7H)-one (first elutingisomer from step 5) using the same two-step procedure as described inSteps 4 and 5 for Intermediate 2. ¹H-NMR (400 MHz, 6d-DMSO): δ ppm 7.67(d, J=8.4 Hz, 1H), 7.29 (s, 2H), 6.52-6.46 (m, 1H), 1.93-1.78 (m, 2H),1.47 (s, 3H), 0.63 (d, J=7.2 Hz, 3H). MS (ES+) C₁₀H₁₂N₂O₂ requires: 192,found: 193 [M+H]⁺.

Steps 8 and 9: The remaining one of (R orS)-2-amino-7-ethyl-7-methylfuro[3,4-b]pyridin-5(7H)-one

The title compound (Intermediate 47) was prepared from the remaining oneof (R or S)-2-chloro-7-ethyl-7-methylfuro[3,4-b]pyridin-5(7H)-one(second eluting isomer from step 5) using the same two-step procedure asdescribed in Steps 4 and 5 for Intermediate 2. ¹H-NMR (400 MHz,6d-DMSO): δ ppm 7.68 (d, J=8.8 Hz, 1H), 7.30 (s, 2H), 6.49 (d, J=8.8 Hz,1H), 1.95-1.79 (m, 2H), 1.48 (s, 3H), 0.64 (d, J=7.4 Hz, 3H). MS (ES+)C₁₀H₁₂N₂O₂ requires: 192, found: 193 [M+H]⁺.

Intermediates 48 and 49:(R)-2-Amino-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one and(S)-2-amino-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

each of which is represented by one of the structures shown below:

which is represented by one of the structures shown below:

which is represented by one of the structures shown below:

Step 1: (R)-2-chloro-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-oneand (S)-2-chloro-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

rac-2-Chloro-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (700 mg,3.54 mmol) was separated by SFC (Daicel Chiralpak IG, MeOH gradient inCO₂ with 0.1% NH₄OH) to give two peaks separately. The first elutingisomer (330 mg, 47% yield) and second eluting isomer (330 mg, 47% yield)were obtained as yellow solids.

Steps 2 and 3: One of (R orS)-2-amino-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

The title compound (Intermediate 48) was prepared from one of (R orS)-2-chloro-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (firsteluting isomer from step 1) using the same two-step procedure asdescribed in Steps 4 and 5 for Intermediate 2. MS (ES+) C₉H₁₀N₂O₂requires: 178, found: 179[M+H]⁺.

Steps 3 and 4: The remaining one of (R orS)-2-amino-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

The title compound (Intermediate 49) was prepared from the remaining oneof (R or S)-2-chloro-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(second eluting isomer from step 1) using the same two-step procedure asdescribed in Steps 4 and 5 for Intermediate 2. MS (ES+) C₉H₁₀N₂O₂requires: 178, found: 179[M+H]⁺.

Intermediates 50 and 51:(R)-2′-Amino-T-methyl-5′H,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridin]-5′-oneand(S)-2′-Amino-7′-methyl-5′H,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridin]-5′-one

each of which is represented by one of the structures shown below:

which is represented by one of the structures shown below:

Step 1: 1-(3-Bromo-6-chloropyridin-2-yl)cyclopropane-1-carbaldehyde

IBX (6.50 g, 10.7 mmol, 46% purity) was added to a solution of(1-(3-bromo-6-chloropyridin-2-yl)cyclopropyl)methanol (2.65 g, 10.1mmol) in EA (80 mL). The reaction mixture was stirred at 80° C. for 1 h,then additional IBX (2.00 g, 3.29 mmol, 46% purity) was added. Thereaction mixture was stirred at 80° C. for 0.5 h, then was filtered andconcentrated to give the title compound (2.60 g, crude) as a yellowsolid that was used without further purification. MS (ES+) C₉H₇BrClNOrequires: 261, found: 262 [M+H]⁺.

Step 2: 1-(1-(3-Bromo-6-chloropyridin-2-yl)cyclopropyl)ethan-1-ol

Methylmagnesium bromide (3 M, 17 mL) was added to a solution of1-(3-bromo-6-chloropyridin-2-yl)cyclopropane-1-carbaldehyde (2.60 g,9.98 mmol) in THE (80 mL) at 0° C. The reaction mixture was stirred for10 min, then was quenched by addition of aqueous saturated NH₄Clsolution (80 mL), diluted with water (40 mL) and extracted with EA (80mL×3). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated to give the title compound (2.70 g,crude) as a yellow oil that was used without further purification. MS(ES+) C₁₀H₁₁N₂O₂ requires: 277, found: 278 [M+H]⁺.

Steps 3-5: tert-Butyl(7′-methyl-5′-oxo-5′H,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridin]-2′-yl)carbamate

The title compound was prepared from1-(1-(3-bromo-6-chloropyridin-2-yl)cyclopropyl)ethan-1-ol using asimilar procedure as described in Steps 4-6 for Intermediate 45 above.¹H NMR (400 MHz, CDCl₃): δ ppm 8.29 (d, J=8.8 Hz, 1H), 7.90 (d, J=8.8Hz, 1H), 7.31 (s, 1H), 4.63-4.53 (m, 1H), 1.61 (s, 3H), 1.53 (s, 9H),1.38-1.35 (m, 1H), 1.09-1.00 (m, 2H).

Step 6: tert-Butyl(R)-(7′-methyl-5′-oxo-5′H,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridin]-2′-yl)carbamateand tert-butyl(S)-(7′-methyl-5′-oxo-5′H,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridin]-2′-yl)carbamate

tert-Butyl(7′-methyl-5′-oxo-5′H,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridin]-2′-yl)carbamate(400 mg) was separated by SFC (column: REGIS (s,s) WHELK-O1 (250 mm×50mm, 10 um), EtOH gradient in CO₂ with 0.1% NH₄OH) to give two separatepeaks. The first eluting isomer (100 mg, 24% yield) and second elutingisomer (140 mg, 34% yield) were obtained as yellow solids.

Step 7: One of (R orS)-2′-amino-7′-methyl-5′H,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridin]-5′-one

TFA (2.31 g, 20.3 mmol) was added to a solution of one of tert-butyl (RorS)-(7′-methyl-5′-oxo-5H′,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridin]-2′-yl)carbamate(first eluting isomer from Step 6, 100 mg) in DCM (6 mL). The reactionmixture was stirred at 25° C. for 30 min, then was quenched withsaturated aqueous NaHCO₃ solution (30 mL) and extracted with DCM (20mL×3). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated to give the title compound(Intermediate 50, 70 mg, crude) as a yellow oil that was used withoutfurther purification. MS (ES+) C₁₁H₁₂N₂O₂ requires: 204, found: 205[M+H]⁺.

Step 8: The remaining one of (R orS)-2′-amino-7-methyl-5′H,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridin]-5′-one

The title compound (Intermediate 51) was prepared from one of tert-butyl(R or S)-(7′-methyl-5′-oxo-5′H,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridin]-2′-yl)carbamate(second eluting isomer from Step 6) using the same procedure asdescribed in Step 7 for Intermediate 50. MS (ES+) C₁₁H12N₂O₂ requires:204, found: 205[M+H]⁺.

Intermediate 52 and 53:(R)-4-(2-Azidobutan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine and(S)-4-(2-azidobutan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine

Intermediates 52 and 53 were made using a similar procedure as describedfor Intermediates 33 and 34, except in step 1, methanol was used. Theracemic title compound (0.84 g, 2.87 mmol) was separated by SFC (column:Daicel Chiralpak IG (250 mm×30 mm, 10 um); mobile phase: [MeOH (with0.1% NH₄OH) in CO₂]) to give:(R)-4-(2-azidobutan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine or(S)-4-(2-azidobutan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine(Intermediate 52, first eluting isomer, 350 mg, 42% yield) as a yellowoil and a second eluting isomer (Intermediate 53, 360 mg, 43% yield) asa yellow solid.

Intermediate 54:2-Amino-7,7-dimethyl-8,9-dihydrooxepino[4,3-b]pyridin-5(7H)-one

Step 1: Methyl(E)-3-(6-((tert-butoxycarbonyl)amino)pyridin-2-yl)acrylate

Pd(OAc)₂ (1.23 g, 5.49 mmol), P(o-tolyl)₃ (2.51 g, 8.24 mmol) anddiisopropylethylamine (71.0 g, 549 mmol, 95.7 mL) were added to asolution of tert-butyl (6-bromopyridin-2-yl)carbamate (15.0 g, 54.9mmol) and methyl acrylate (18.9 g, 220 mmol, 19.8 mL) in DMF (150 mL).The reaction mixture was stirred at 100° C. for 1 h, then was diluted EA(200 mL) and washed with brine (200 mL×3). The organic layers were driedover sodium sulfate, filtered and concentrated to give a residue. Theresidue was purified by flash-column chromatography on silica gel(gradient elution, 10% to 33% EA-petroleum ether) to give the titlecompound (7.00 g, 39% yield) as a yellow solid.

Step 2: Methyl 3-(6-((tert-butoxycarbonyl)amino)pyridin-2-yl)propanoate

Pd/C (100 mg, 10% purity) was added to a solution of methyl(E)-3-(6-((tert-butoxycarbonyl)amino)pyridin-2-yl)acrylate (7.00 g, 25.2mmol) in MeOH (100 mL). The mixture was stirred at 25° C. for 12 h underhydrogen, then was filtered and concentrated to give a residue. Theresidue was purified by flash-column chromatography on silica gel(gradient elution, 10% to 33% EA-petroleum ether) to give the titlecompound (6.00 g, 18.6 mmol, 74% yield) as a yellow solid.

Step 3: tert-Butyl (6-(3-hydroxy-3-methylbutyl)pyridin-2-yl)carbamate

Methyl magnesium bromide (3 M, 35.7 mL) was added to a solution ofmethyl 3-(6-Wert-butoxycarbonyl)amino)pyridin-2-yl)propanoate (6.00 g,21.4 mmol) in THF (100 mL) at 0° C. The reaction mixture was stirred at25° C. for 0.5 h, then was poured into water (200 mL) and extracted withEA (50 mL×3). The combined organic layers were dried over sodiumsulfate, filtered, and concentrated to give a residue. The residue waspurified by flash-column chromatography on silica gel (gradient elution,15% to 50% EA-PE) to give the title compound (5.00 g, 15.9 mmol, 74%yield) as a yellow solid.

Step 4: tert-Butyl(5-bromo-6-(3-hydroxy-3-methylbutyl)pyridin-2-yl)carbamate

N-Bromosuccinimide (3.17 g, 17.8 mmol) in ACN (50 mL) was added to asolution of tert-butyl(6-(3-hydroxy-3-methylbutyl)pyridin-2-yl)carbamate (5.00 g, 17.8 mmol)in ACN (50 mL) at 0° C. The reaction mixture was stirred at 25° C. for 1h, then was poured into water (200 mL) and extracted with EA (50 mL×3).The combined organic layers were dried over sodium sulfate, filtered,and concentrated to give a residue. The residue was purified byflash-column chromatography on silica gel (gradient elution, 10% to 33%EA-petroleum ether) to give the title compound (4.00 g, 62% yield) as ayellow solid. ¹H-NMR (400 MHz, CDCl₃): δ ppm 7.72 (d, J=8.4 Hz, 1H),7.65 (d, J=8.8 Hz, 1H), 7.39 (S, 1H), 2.99-2.93 (m, 2H), 1.87-1.78 (m,2H), 1.49 (s, 9H), 1.27 (s, 6H).

Step 5:6-((tert-Butoxycarbonyl)amino)-2-(3-hydroxy-3-methylbutyl)nicotinic acid

n-Butyllithium (2.5 M, 11.1 mL) was added to a solution of tert-butyl(5-bromo-6-(3-hydroxy-3-methylbutyl)pyridin-2-yl)carbamate (2.00 g, 5.57mmol) in THF (50 mL) at −78° C. The reaction mixture was stirred at −78°C. for 10 min, then carbon dioxide was added and the mixture was stirredat −78° C. for 20 min. The reaction mixture was then poured into water(100 mL) and extracted with EA (30 mL×3). The organic layers werediscarded and aqueous ammonium chloride solution was added to theaqueous layer to adjust pH<7. The mixture was extracted with EA (30mL×5), and the combined organic layers was dried over sodium sulfate,filtered and concentrated to give the title compound (200 mg, crude) asa yellow solid.

Step 6: tert-Butyl(7,7-dimethyl-5-oxo-5,7,8,9-tetrahydrooxepino[4,3-b]pyridin-2-yl)carbamate

Dicyclohexylcarbodiimide (229 mg, 1.11 mmol, 225 μL) was added to asolution of6-((tert-butoxycarbonyl)amino)-2-(3-hydroxy-3-methylbutyl)nicotinic acid(180 mg, crude) and 4-N,N-dimethylaminopyridine (33.9 mg, 277 μmol) inDCM (20 mL). The reaction mixture was stirred at 25° C. for 12 h, thenwas concentrated to give the residue. The residue purified by prep-TLCon silica gel (33% EA-petroleum ether) to give the title compound (30.0mg, crude) as a yellow solid.

Step 7: 2-Amino-7,7-dimethyl-8,9-dihydrooxepino[4,3-b]pyridin-5(7H)-one

The title compound was prepared from tert-butyl(7,7-dimethyl-5-oxo-5,7,8,9-tetrahydrooxepino[4,3-b]pyridin-2-yl)carbamateusing a similar procedure as describe in Step 7 of Intermediate 50.¹H-NMR (400 MHz, CDCl₃): δ ppm 7.92 (d, J=8.8 Hz, 1H), 6.36 (d, J=8.8Hz, 1H), 5.17 (s, 2H), 2.96-2.92 (m, 2H), 2.11-2.09 (m, 2H), 1.33 (s,6H).

Intermediate 55:2-Amino-8,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

Step 1: Methyl 2-(3-bromo-6-chloropyridin-2-yl)-2-methylpropanoate

Sodium hydride (2.91 g, 72.8 mmol, 60% purity) was added to a solutionof methyl 2-(3-bromo-6-chloropyridin-2-yl)acetate (5.50 g, 20.8 mmol) inTHE (20 mL) at 0° C. The reaction mixture was stirred for 15 minutes at0° C., then iodomethane (7.38 g, 51.9 mmol) was added. The reactionmixture was warmed to 25° C. and stirred for 45 min, then was quenchedwith water (30 mL) and extracted with EA (30 mL×2). The combined organiclayers were concentrated to give a residue. The residue was purified byflash-column chromatography on silica gel (gradient elution, 0% to 10%EA-petroleum ether) to give the title compound (5.5 g, 90% yield) as ayellow oil. ¹H NMR (400 MHz, CD₃OD): δ ppm 7.97 (d, J=8.4 Hz, 1H), 7.20(d, J=8.4 Hz, 1H), 3.95 (s, 2H), 1.50 (s, 6H)

Steps 2-6:2-Amino-8,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

The title compound was prepared using similar procedures as described inSteps 3-6 of Intermediate 45 and Step 7 of Intermediate 50. MS (ES+)C₁₀H₁₂N₂O₂ requires: 192, found: 193 [M+H]⁺. ¹H NMR (400 MHz, 6d-DMSO):δ ppm 7.77 (d, J=8.8 Hz, 1H), 7.01 (s, 2H), 6.40 (d, J=8.8 Hz, 1H), 4.15(s, 2H), 1.21 (s, 6H).

Intermediates 56 and 57:(R)-2-Amino-7,8,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-oneand(S)-2-amino-7,8,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

Steps 1-5:(rac)-2-Amino-7,8,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

The title compound was prepared from2-(3-bromo-6-chloropyridin-2-yl)-2-methylpropan-1-ol using a similarprocedure as described in Steps 1-5 of Intermediate 50. C₁₁H₁₄N₂O₂requires: 206, found: 207 [M+H]⁺.

Step 6:(R)-2-Amino-7,8,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-oneand(S)-2-amino-7,8,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

(rac)-2-Amino-7,8,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(120 mg) was separated by SFC (column: REGIS (s,s) WHELK-O1 (250 mm×50mm, 10 um), MeOH gradient in CO₂ with 0.1% NH₄OH) to give two peaksseparately. The first eluting isomer, one of (R orS)-2-Amino-7,8,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(Intermediate 56, 60 mg, 50% yield) and second eluting isomer, one of (Ror S)-2-Amino-7,8,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(Intermediate 5760 mg, 50% yield) were obtained as yellow solids.

Intermediates 58 and 59:(7R,8R)-2-Amino-8-ethyl-7-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-oneand(7S,8S)-2-amino-8-ethyl-7-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

each of which is represented by one of the structures shown below:

which is represented by one of the structures shown below:

Step 1: Methyl 2-(3-bromo-6-chloropyridin-2-yl)butanoate

NaH (1.69 g, 42.2 mmol, 60 wt %) was added to a solution of methyl2-(3-bromo-6-chloropyridin-2-yl)acetate (9.3 g, 35.2 mmol) in THE (100mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h,iodoethane (6.03 g, 38.9 mmol) was added to the reaction mixture. Thereaction mixture was stirred for 30 min, then was quenched by additionof aqeuous NH₄Cl solution (20 mL) and extracted with EA (20 mL×3). Thecombined organic layers were concentrated under reduced pressure to givea residue. The aqueous layer was also concentrated to give a residue.That residue was dissolved in EA (500 mL), filtered and concentrated togive a residue. The residues were purified by flash-columnchromatography on silica gel (gradient elution, 0% to 20% EA-PE) to givethe title compound (6.5 g, 63% yield) as a colorless oil. ¹H NMR (400MHz, CDCl₃): δ ppm 7.71 (d, J=8.4 Hz, 1H), 7.04-7.01 (m, 1H), 4.12-4.03(m, 1H), 3.62 (s, 3H), 2.14-2.09 (m, 1H), 2.02-1.96 (m, 1H), 0.89-0.84(m, 3H).

Steps 2-7: tert-Butyl(8-ethyl-7-methyl-5-oxo-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)carbamate

The title compound was prepared from methyl2-(3-bromo-6-chloropyridin-2-yl)butanoate using a similar procedure asdescribed in Step 3 of Intermediate 45 and Steps 1-5 of Intermediate 50.

Step 8: tert-Butyl((7R,8R)-8-ethyl-7-methyl-5-oxo-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)carbamateand tert-butyl((7S,8S)-8-ethyl-7-methyl-5-oxo-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)carbamate

tert-Butyl(8-ethyl-7-methyl-5-oxo-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)carbamate(200 mg) was separated by SFC (column: Daicel Chiralpak AD-H (250 mm×30mm, 5 um), IPA gradient in CO₂ with 0.1% NH₄OH) to give two peaksseparately. The first eluting isomer (80 mg, 40% yield) and secondeluting isomer (70 mg, 35% yield) were obtained as colorless oils

Step 9: One of (7R,8R or7S,8S)-2-amino-8-ethyl-7-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

The title compound (Intermediate 58) was prepared from one of tert-butyl((7R,8R or7S,8S)-8-ethyl-7-methyl-5-oxo-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)carbamate(first eluting isomer from Step 8) using the same procedure as describedin Step 7 for Intermediate 50. MS (ES+) C₁₁H₁₄N₂O₂ requires: 206, found:207[M+H]⁺.

Step 10: The remaining one of (7R,8R or7S,8S)-2-amino-8-ethyl-7-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

The title compound (Intermediate 59) was prepared from one tert-butyl((7R,8R or7S,8S)-8-ethyl-7-methyl-5-oxo-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)carbamate(second eluting isomer from Step 8) using the same procedure asdescribed in Step 7 for Intermediate 50. MS (ES+) C₁₁H₁₄N₂O₂ requires:206, found: 207[M+H]⁺.

Intermediates 60 and 61:(7S,8R)-2-Amino-7-ethyl-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-oneand(7R,8S)-2-amino-7-ethyl-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

each of which is represented by one of the structures shown below:

which is represented by one of the structures shown below:

which is represented by one of the structures shown below:

Steps 1-2: (7S,8R and7R,8S)-7-Ethyl-2-methoxy-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

The title compound was prepared from(Z)-4,4,5,5-tetramethyl-2-(pent-2-en-2-yl)-1,3,2-dioxaborolane andmethyl 2-chloro-6-methoxynicotinate using a similar procedure asdescribed above of Intermediate 17, except CsF was used as a base inStep 1 and Step 2 was conducted at 60° C. for 2 h. The product mixture(4 compounds, cis and trans racemates) was purified by prep-HPLC[column: Phenomenex luna C18 250*80 mm*10 um; mobile phase:[water(0.225% FA)-ACN]; B %: 45%-75%, 25 min] to give the title compound(trans, racemic, 2 g, 27% yield) as a white solid. ¹H NMR (400 MHz,CDCl₃): δ ppm 8.19 (d, J=8.4 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 4.27-4.22(m, 1H), 4.01 (m, 3H), 3.10-2.97 (m, 1H), 1.91-1.85 (m, 1H), 1.84-1.78(m, 1H), 1.42 (d, J=7.2 Hz, 3H), 1.13-1.08 (m, 3H)

Steps 3-4: (7S,8R and7R,8S)-2-Chloro-7-ethyl-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

The title compound was prepared from (7S,8R and7R,8S)-7-ethyl-2-methoxy-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-oneusing the same procedure as described in Steps 4 and 5 for Intermediate10.

Step 5:(7S,8R)-2-Chloro-7-ethyl-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-oneand(7R,8S)-2-chloro-7-ethyl-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

(7S,8R and7R,8S)-2-Chloro-7-ethyl-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(255 mg, 1.13 mmol) was separated by SFC (Daicel Chiralpak AD, MeOHgradient in CO₂ with 0.1% NH₄OH) to give two peaks separately. The firsteluting isomer (100 mg, 39% yield) and second eluting isomer (120 mg,47% yield) were obtained as yellow solids. ¹H NMR (400 MHz, CDCl₃): δppm 8.29 (d, J=8.4 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 4.36-4.31 (m, 1H),3.19-3.12 (m, 1H), 1.87-1.75 (m, 2H), 1.46 (d, J=7.2 Hz, 3H), 1.11-1.08(m, 3H).

Steps 6 and 7: One of (7S,8R)- or(7R,8S)-2-amino-7-ethyl-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

The title compound (Intermediate 60) was prepared from one of (7S,8R)-or(7R,8S)-2-chloro-7-ethyl-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(first eluting isomer from step 5) using the same two-step procedure asdescribed in Steps 4 and 5 for Intermediate 2. MS (ES+) C₁₁H₁₄N₂O₂requires: 206, found: 207[M+H]⁺.

Steps 8 and 9: The remaining one of (7S,8R)- or(7R,8S)-2-amino-7-ethyl-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

The title compound (Intermediate 60) was prepared from one of (7S,8R)-or(7R,8S)-2-chloro-7-ethyl-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(second eluting isomer from step 5) using the same two-step procedure asdescribed in Steps 4 and 5 for Intermediate 2. MS (ES+) C₁₁H₁₄N₂O₂requires: 206, found: 207[M+H]⁺.

Intermediate 62:2-Amino-7,7-dimethyl-7,8-dihydro-1,6-naphthyridin-5(6H)-one

Step 1: tert-Butyl2-hydroxy-7,7-dimethyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

A mixture of tert-butyl 2,2-dimethyl-4-oxopiperidine-1-carboxylate (4.00g, 17.6 mmol) and pyrrolidine (1.25 g, 17.6 mmol) were dissolved intoluene (60 mL), and the solution was heated to 140° C. in a vesselcapped with a Dean-Stark trap for 5 h. The mixture was concentrated,then the residue was dissolved in toluene (60 mL) and prop-2-ynamide(1.82 g, 26.4 mmol) was added. The reaction mixture was heated to 140°C. for 16 h, then was concentrated to give a residue. The residue waspurified by prep-HPLC: reverse phase [ACN/(0.1% TFA in water), 0% to50%] to give the title compound (500 mg, 9.5% yield, 93% purity) asbrown oil. ¹H-NMR (400 MHz, CD₃OD): δ ppm 7.45 (d, J=9.6 Hz, 1H),6.54-6.47 (m, 1H), 4.20 (s, 2H), 2.85 (s, 2H), 1.52-1.48 (m, 9H).

Step 2: 2-Chloro-7,7-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridine

The title compound was prepared from tert-butyl2-hydroxy-7,7-dimethyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylateusing a similar procedure as described in Step 2 of Intermediate 2.

Step 3: tert-Butyl2-chloro-7,7-dimethyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

A mixture of 2-chloro-7,7-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridine(300 mg, 1.53 mmol), sodium hydroxide (305 mg, 7.63 mmol), and Boc₂O(665 mg, 3.05 mmol) in water (50 mL) and EtOH (5.0 mL) was stirred at20° C. for 0.5 h. The reaction mixture was extracted with EA (30 mL×3),and the combined organic layers were washed with water, brine, driedover anhydrous sodium sulfate and concentrated to give a residue. Theresidue was purified by flash-column chromatography on silica gel(gradient elution, 1% to 25% EA-petroleum ether) to give the titlecompound (250 mg, 798 umol) as yellow oil.

Steps 4-6: 2-Amino-7,7-dimethyl-7,8-dihydro-1,6-naphthyridin-5(6H)-one

The title compound was prepared from tert-butyl2-chloro-7,7-dimethyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylateusing a similar procedure as described in Steps 3-5 of Intermediate 2.¹H NMR (400 MHz, CDCl₃): δ ppm 8.06 (d, J=8.4 Hz, 1H), 6.44 (d, J=8.4Hz, 1H), 5.48 (s, 1H), 4.80 (s, 2H), 2.89 (s, 2H), 1.34 (s, 6H).

Intermediates 63 and 64:(R)-4-(1-Azido-1-cyclobutylethyl)-6-chloro-1-cyclopropoxy-2,7-naphthyridineand(S)-4-(1-azido-1-cyclobutylethyl)-6-chloro-1-cyclopropoxy-2,7-naphthyridine

Intermediates 63 and 64 were made using a similar procedure as describedfor Intermediates 33 and 34, except in step 4, cyclobutylmagnesiumbromide was used and the reaction was stirred at 60° C. for 1 h. Theracemic title compound was separated by SFC(column: Daicel Chiralpak AY(250 mm×50 mm, 10 um); mobile phase: [EtOH (with 0.1% NH₄OH) in CO₂]) togive(R)-4-(1-azido-1-cyclobutylethyl)-6-chloro-1-cyclopropoxy-2,7-naphthyridineor(S)-4-(1-azido-1-cyclobutylethyl)-6-chloro-1-cyclopropoxy-2,7-naphthyridine(Intermediate 63, first eluting isomer, 27 mg, 18% yield) as a whitesolid and a second eluting isomer(R)-4-(1-azido-1-cyclobutylethyl)-6-chloro-1-cyclopropoxy-2,7-naphthyridineor(S)-4-(1-azido-1-cyclobutylethyl)-6-chloro-1-cyclopropoxy-2,7-naphthyrid(Intermediate 64, 67 mg, 45% yield) as a white solid.

Intermediates 65 and 66:(1S,3S)-3-(4-Aminopyrimidin-2-yl)cyclohexan-1-ol or(1R,3R)-3-(4-aminopyrimidin-2-yl)cyclohexan-1-ol

Step 1: 3-(4-Aminopyrimidin-2-yl)cyclohex-2-en-1-one

Potassium carbonate (600 mg, 4.34 mmol) and Pd(dppf)Cl₂ (160 mg, 218umol) were added to a mixture of 2-chloropyrimidin-4-amine (280 mg, 2.16mmol) and3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-one (500mg, 2.25 mmol) in dioxane (10 mL) and water (3 mL). The reaction mixturewas stirred at 90° C. for 16 h, then was poured into water (30 mL) andextracted with EA (50 mL×3). The organic layers were combined, driedover anhydrous sodium sulfate, filtered, and concentrated under reducedpressure to give a residue. The residue was purified by columnchromatography [SiO₂, Petroleum ether/Ethyl acetate=2/1 to 1:2] to givethe title compound (300 mg, 73.4% yield) as a yellow solid.

Step 2: 3-(4-Aminopyrimidin-2-yl)cyclohex-2-en-1-ol

NaBH₄ (120 mg, 3.17 mmol) was added to a mixture of3-(4-aminopyrimidin-2-yl)cyclohex-2-en-1-one (300 mg, 1.59 mmol) in MeOH(2 mL). The reaction mixture was stirred at 20° C. for 1 h, then wasquenched with water (10 mL) and concentrated to give a residue. Theresidue was washed with DCM (10 mL) and filtered, and the filtrate wasconcentrated to give the title compound (290 mg, crude) as a yellowsolid.

Step 3: rac-(1S,3S)-3-(4-Aminopyrimidin-2-yl)cyclohexan-1-ol

Pd/C (20 mg, 0.304 mmol) was added to a solution of3-(4-aminopyrimidin-2-yl)cyclohex-2-en-1-ol (290 mg, 1.52 mmol) in MeOH(10 mL) and the reaction mixture was stirred at 20° C. for 4 h underhydrogen (50 psi). The reaction mixture was then filtered andconcentrated to give a residue. The residue contained a mixture of cisand trans products which were separated by prep-HPLC (column: WelchUltimate AQ-C18 150*30 mm*5 um; mobile phase: [water(0.1% TFA)-ACN]; B%: 2%-22%, 13 min). WH103959-6 (350.0 mg, 1.81 mmol, 58% yield) to givethe title compound as a TFA salt. The TFA salt of the title compound(7.50 g, 24.41 mmol, from several batches) in MeOH (150 mL) was treatedwith basic resin (Ambersep 900) (100 g) and stirred for 12 h at 25° C.The mixture was filtered and the filtrate was concentrated to give thetitle compound (5.40 g, crude) as a white solid.

Step 4: (1S,3S)-3-(4-Aminopyrimidin-2-yl)cyclohexan-1-ol and(1R,3R)-3-(4-aminopyrimidin-2-yl)cyclohexan-1-ol

rac-(1S,3S)-3-(4-Aminopyrimidin-2-yl)cyclohexan-1-ol (700 mg) wasseparated by SFC (column: ChiralPak IC (250 mm*30 mm, 10 um); mobilephase: [0.1% NH₃H₂O IPA]; B %). To give(1S,3S)-3-(4-aminopyrimidin-2-yl)cyclohexan-1-ol or(1R,3R)-3-(4-aminopyrimidin-2-yl)cyclohexan-1-ol (Intermediate 65, firsteluting isomer, 315 mg, 45% yield) as a white solid and(1S,3S)-3-(4-aminopyrimidin-2-yl)cyclohexan-1-ol or(1R,3R)-3-(4-aminopyrimidin-2-yl)cyclohexan-1-ol (Intermediate 66,second eluting isomer, 320 mg, 45% yield) as a white solid. MS (ES+)C₁₀H₁₅N₃O requires: 193, found: 194[M+H]⁺.

Intermediate 67:(S)-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine

Step 1: 6-Chloro-1-methoxy-4-(prop-1-en-2-yl)-2,7-naphthyridine

The title compound was prepared from4-bromo-6-chloro-1-methoxy-2,7-naphthyridine and2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane using the sameprocedure described in Step 1 of Example 13.

Step 2: 2-(6-Chloro-1-methoxy-2,7-naphthyridin-4-yl)propane-1,2-diol

OsO4 (1.02 g, 4.01 mmol) was added to a mixture of6-chloro-1-methoxy-4-(prop-1-en-2-yl)-2,7-naphthyridine (9.4 g, 40.0mmol) and NMO (9.38 g, 80.1 mmol) in acetone (160 mL) and H₂O (40 mL).The reaction mixture was stirred at 25° C. for 12 h, then was quenchedsaturated aqueous KF solution (150 mL) and filtered. The solution wasextracted with EA (2×300 mL). The organic phase was dried over Na₂SO₄,filtered and concentrated to give the title compound (9.3 g, 86% yield)as yellow oil which was used in the next step without furtherpurification.

Step 3:6-Chloro-4-(1,2-dimethoxypropan-2-yl)-1-methoxy-2,7-naphthyridine

NaH (4.85 g, 121 mmol, 60% purity) was added to a solution of2-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)propane-1,2-diol (9.3 g,34.6 mmol) in THE (150 mL). The reaction mixture was stirred at 25° C.for 0.5 h, then MeI (12.3 g, 86.5 mmol) was added. The reaction mixturewas stirred at 25° C. for 0.5 h, and then stirred at 40° C. for 2 h. Thereaction mixture was then added into a stirring solution of thesaturated aqueous NH₄Cl (50 mL) and extracted with EA (300 mL). Theorganic layer was washed with saturated aqueous NH₄Cl (100 mL×3), driedover Na₂SO₄, filtered and concentrated to give the title compound (10 g,85% yield) as a yellow oil which was used in the next step withoutfurther purification.

Step 4:4-(2-Azido-1-methoxypropan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine

BF₃.Et₂O (8.80 g, 62.0 mmol) was added to a mixture of6-chloro-4-(1,2-dimethoxypropan-2-yl)-1-methoxy-2,7-naphthyridine (9.2g, 31.0 mmol), TMSN₃ (17.9 g, 155 mmol) in DCE (150 mL) at 25° C. Thereaction mixture heated to 60° C. for 6 h under N₂. The reaction mixturewas then added into a stirring solution of aqueous saturated NaHCO₃ (300mL) and extracted with EA (300 mL). The organic layer was dried overNa₂SO₄, filtered and concentrated to give a residue. The residue waspurified by flash-column chromatography on silica gel (20% EA-PE) togive the title compound (8 g, 73% yield) as a colorless oil.

Step 4:(R)-4-(2-Azido-1-methoxypropan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridineand(S)-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine

The title compound was prepared by chiral SFC separation of4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine(column: Daicel ChiralPak IG (250*30 mm, 10 um); mobile phase: [15% (IPAwith 0.1% NH₄OH)] to give two isomers. The first isomer to elute was(R)-4-(2-Azido-1-methoxypropan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridineand the second isomer to elute was the title compound,(S)-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine.The isomers were determined by X-ray crystal structure of a compoundwhich was derived from the second isomer.

Intermediate 68 and 69:(S)-4-(2-Azido-1-methoxypropan-2-yl)-6-chloro-1-cyclopropoxy-2,7-naphthyridineand(R)-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-cyclopropoxy-2,7-naphthyridine

Step 1:rac-2-(6-Chloro-1-cyclopropoxy-2,7-naphthyridin-4-yl)propane-1,2-diol

Sulfuric acid (106 mg, 1.08 mmol, 57.8 uL) was added to a solution of6-chloro-1-cyclopropoxy-4-(2-methyloxiran-2-yl)-2,7-naphthyridine(prepared as described in Step 2 of Example 13, 300 mg, 1.08 mmol) inTHF (2 mL) and water (0.5 mL). The reaction mixture was stirred at 60°C. for 1 h, then was poured into water (100 mL) and extracted with EA(30 mL×3). The organic layers were dried over sodium sulfate, filteredand concentrated to give a residue. The residue was purified by columnchromatography (SiO₂, PE:EA=5:1 to 1:1) to give the title compound (250mg, 78% yield) as a white solid.

Step 2:rac-2-(6-Chloro-1-cyclopropoxy-2,7-naphthyridin-4-yl)-1-methoxypropan-2-ol

NaH (40.7 mg, 1.02 mmol, 60% purity) was added to a solution of2-(6-chloro-1-cyclopropoxy-2,7-naphthyridin-4-yl)propane-1,2-diol (200mg, 679 μmol) in THF (5 mL) at 0° C. The reaction mixture was stirred at0° C. for 0.5 h, then methyl iodide (289 mg, 2.04 mmol, 127 uL) wasadded. The cooling bath was removed and the reaction mixture was stirredat 25° C. for 0.5 h, then was poured into water (100 mL) and extractedwith EA (30 mL×3). The organic layers were dried over sodium sulfate,filtered and concentrated to give a residue. The residue was purified bycolumn chromatography (SiO₂, PE:EA=5:1 to 1:1) to give the titlecompound (70.0 mg, 33% yield) as a yellow solid.

Step 3:rac-4-(2-Azido-1-methoxypropan-2-yl)-6-chloro-1-cyclopropoxy-2,7-naphthyridine

TMSN₃ (93.3 mg, 106 uL) and InBr₃ (287.06 mg, 810 μmol) were added to asolution of2-(6-chloro-1-cyclopropoxy-2,7-naphthyridin-4-yl)-1-methoxypropan-2-ol(50.0 mg, 162 μmol) in DCE (2 mL). The reaction mixture was stirred at50° C. for 2 h, then was poured into water (100 mL) and saturatedaqueous sodium bicarbonate solution was added to adjust to pH>7. Themixture was extracted with EA (20 mL×3), the organic layers were driedover sodium sulfate, filtered and concentrated to give a residue. Theresidue purified by prep-TLC (PE:EA=2:1) to obtain give the titlecompound (40.0 mg, crude) as a yellow solid.

Step 4:(S)-4-(2-Azido-1-methoxypropan-2-yl)-6-chloro-1-cyclopropoxy-2,7-naphthyridineand(R)-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-cyclopropoxy-2,7-naphthyridine

Rac-4-(2-Azido-1-methoxypropan-2-yl)-6-chloro-1-cyclopropoxy-2,7-naphthyridine(0.35 g, 1.05 mmol) was separated by SFC (column: Daicel Chiralpak IG(250 mm*30 mm, 10 um); mobile phase: [0.1% NH₃H₂O in MeOH]) to give(S)-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-cyclopropoxy-2,7-naphthyridineor(R)-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-cyclopropoxy-2,7-naphthyridine(Intermediate 68, first eluting isomer, 150 mg, 446 umol, 43% yield) aswhite solid and(S)-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-cyclopropoxy-2,7-naphthyridineor(R)-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-cyclopropoxy-2,7-naphthyridine(Intermediate 69, second eluting isomer, 140 mg, 417 umol, 40% yield) asa white solid. MS (ES+) C₁₅H₁₆ClN₅O₂ requires: 333, found: 334[M+H]⁺.

Intermediate 70:(S)-4-(2-Azido-1-methoxypropan-2-yl)-6-chloro-1-methyl-2,7-naphthyridine

Step 1:(S)-4-(2-Azido-1-methoxypropan-2-yl)-6-chloro-2,7-naphthyridin-1-ol

Aqueous HCl (6 M, 5.41 mL) was added to a solution of(S)-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine(Intermediate 67) (3 g, 9.75 mmol) in THE (240 mL). The mixture wasstirred at 25° C. for 12 h, then was adjusted to pH ˜8 with addition ofsolid NaHCO₃. The mixture was extracted with EA (2×150 mL) and theorganic layer was dried over Na₂SO₄, filtered and concentrated to givethe title compound (2.7 g, 83% yield, 88% purity) as a white solid whichwas used in the next step without further purification.

Step 2:(S)-4-(2-Azido-1-methoxypropan-2-yl)-1,6-dichloro-2,7-naphthyridine

POCl₃ (3.34 g, 21.8 mmol) was added to a mixture of(S)-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-2,7-naphthyridin-1-ol(1.28 g, 4.36 mmol) and TEA (1.16 g, 11.5 mmol) in MCCN (20 mL). Themixture was heated to 100° C. for 12 h. The reaction mixture was thenadded to saturated aqueous NH₄Cl (50 mL) and extracted with EA (100mL×3). The organic layers were combined and dried over Na₂SO₄, filtered,and concentrated to give a residue. The residue was purified byflash-column chromatography on silica gel (25% EA-PE) to give the titlecompound (1.2 g, 88% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃): δppm 9.61 (s, 1H), 8.57 (s, 1H), 8.48 (s, 1H), 3.98 (d, J=9.6 Hz, 1H),3.78 (d, J=9.6 Hz, 1H), 3.41 (s, 3H), 1.80 (s, 3H).

Step 3:(S)-4-(2-Azido-1-methoxypropan-2-yl)-6-chloro-1-methyl-2,7-naphthyridine

Ad₂nBuP Pd G3 (cataCXium® A Pd G3) (81.6 mg, 112 μmol) and potassiumphosphate (714 mg, 3.36 mmol) were added to a mixture of(S)-4-(2-azido-1-methoxypropan-2-yl)-1,6-dichloro-2,7-naphthyridine (350mg, 1.12 mmol) and methylboronic acid (73.8 mg, 1.23 mmol) in THE (5mL). The reaction mixture was stirred at 60° C. for 2 h, then wasdiluted with water (40 mL) and extracted with EA (40 mL×3). The combinedorganic layers were dried over anhydrous sodium sulfate, filtered andconcentrated to give a residue. The residue was purified by flash-columncolumn chromatography on silica gel (PE/EA=10/1 to 1/1) to give thetitle compound (220 mg, 67% yield) as a white solid. MS (ES+)C₁₃H₁₄ClN₅O requires: 291, found: 292[M+H]⁺.

Intermediates 71 and 72:(S)—N—((S)-1-(6-Chloro-1-methyl-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamideand(S)—N—((R)-1-(6-chloro-1-methyl-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide

Step 1: 6-Chloro-1-methoxy-4-vinyl-2,7-naphthyridine

The title compound was prepared from4-bromo-6-chloro-1-methoxy-2,7-naphthyridine and4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane using a similarprocedure as described in Step 1 of Example 13. MS (ES+) C₁₁H₉ClN₂Orequires: 220, found: 221 [M+H]⁺.

Steps 2-4: 6-Chloro-1-methyl-4-vinyl-2,7-naphthyridine

The title compound was prepared from6-chloro-1-methoxy-4-vinyl-2,7-naphthyridine using a similar procedureas described in Steps 1-3 of Intermediate 70. MS (ES+) C₁₁H₉ClN₂requires: 204, found: 205 [M+H]⁺.

Step 5: 6-Chloro-1-methyl-2,7-naphthyridine-4-carbaldehyde

A solution of 6-chloro-1-methyl-4-vinyl-2,7-naphthyridine (400 mg, 1.95mmol) in MeOH (3 mL) and DCM (30 mL) was cooled to −78° C. Ozone wasbubbled into the reaction mixture, and after 10 min nitrogen gas wasbubbled through the reaction mixture. Me₂S (364 mg, 5.86 mmol) was addedto the reaction mixture, and the mixture was stirred at 25° C. for 50min. The reaction mixture was then concentrated to give a residue, andthe residue was purified by column chromatography (SiO₂, PE:EA=1/0 to0/1) to give the title compound (330 mg, 78% yield) as a yellow solid.MS (ES+) C₁₀H₇ClN₂O requires: 206, found: 207[M+H]⁺. ¹H NMR (400 MHz,CD₃OD): δ ppm 10.29 (s, 1H), 9.50 (s, 1H), 9.12 (s, 1H), 8.99 (s, 1H),3.15 (s, 3H).

Step 6:(S)—N-((6-Chloro-1-methyl-2,7-naphthyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide

MgSO₄ (576 mg, 4.79 mmol) and Ti(i-PrO)₄ (2.72 g, 9.58 mmol, 2.83 mL)were added to a solution of6-chloro-1-methyl-2,7-naphthyridine-4-carbaldehyde (330 mg, 1.60 mmol)and (S)-2-methylpropane-2-sulfinamide (580 mg, 4.79 mmol) in THF (10mL). The reaction mixture was stirred at 60° C. for 12 h, then wasdiluted with water (70 ml) and EA (150 ml), stirred at 25° C. for 10min, then filtered. The filtrate was extracted with EA (70 ml×3), andthe combined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated give a residue. The residue was purified byflash-column chromatography on silica gel (gradient elution, 0-60%EA/PE) to give the title compound (300 mg, 58% yield) as a yellow solid.MS (ES+) C₁₄H₁₆ClN₃OS requires: 309, found: 310[M+H]⁺.

Step 7:(S)—N—((S)-1-(6-Chloro-1-methyl-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamideand(S)—N—((R)-1-(6-chloro-1-methyl-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide

EtMgBr (3 M, 915 uL) was added to a solution of(S)—N-((6-chloro-1-methyl-2,7-naphthyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide(170 mg, 549 umol) in THF (20 mL) at 25° C. The reaction mixture wasstirred at 25° C. for 30 min, then was quenched by addition of saturatedaqueous NH₄Cl solution (40 mL) and extracted with EA (40 mL×3). Thecombined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated to give a residue. The residue was purified byprep-HPLC (column: Phenomenex Gemini-NX C18 75×30 mm×3 um; mobile phase:[water (0.05% ammonia hydroxide v/v)-ACN]; B %: 18%-48%, 11.5 min) togive the title compounds separately. The stereochemistry at the ethylamine stereocenter was arbitrarily assigned.

Peak 1 (Intermediate 71):(S)—N—((S)-1-(6-Chloro-1-methyl-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamideor(S)—N—((R)-1-(6-chloro-1-methyl-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(55 mg, 22% yield) as a yellow oil. MS (ES+) C₁₆H₂₂ClN₃OS requires: 339,found: 340[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ ppm 9.43 (d, J=0.8 Hz, 1H),8.59 (s, 1H), 8.07 (s, 1H), 4.91-4.73 (m, 1H), 4.17-4.08 (m, 1H),3.60-3.50 (m, 1H), 3.05 (s, 3H), 2.13-2.07 (m, 1H), 2.03 (s, 1H), 1.20(s, 9H), 0.96-0.89 (m, 3H).Peak 2 (Intermediate 72):(S)—N—((S)-1-(6-Chloro-1-methyl-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamideor(S)—N—((R)-1-(6-chloro-1-methyl-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(55 mg, 26% yield) as a yellow oil. MS (ES+) C₁₆H₂₂ClN₃OS requires: 339,found: 340[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ ppm 9.43 (d, J=0.4 Hz, 1H),8.61 (s, 1H), 8.06 (s, 1H), 4.88-4.81 (m, 1H), 4.18-4.05 (m, 1H),3.79-3.68 (m, 2H), 3.58-3.53 (d, J=3.18 Hz, 1H), 3.05 (s, 3H), 2.28-2.18(m, 1H), 2.14-2.01 (m, 1H), 1.24 (s, 9H), 0.90-0.86 (m, 3H).

Intermediates 73 and 74:(S)—N—((S)-1-(3-Chloro-8-methoxyisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamideand(S)—N—((R)-1-(3-chloro-8-methoxyisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamide

Step 1: (E)-2-(Hydroxyimino)-7-methoxy-2,3-dihydro-1H-inden-1-one

t-BuONO (67.9 g, 659 mmol, 78.4 mL, 1.10 eq) was added to a solution of7-methoxy-2,3-dihydro-1H-inden-1-one (99.0 g, 599 mmol, 1.00 eq) in THE(500 mL) at −10-0° C., followed by dropwise addition of HCl (4 M inMeOH, 15.0 mL, 0.10 eq) to the mixture at −10-0° C. The reaction mixturewas stirred at 0° C. for 2 h, then was concentrated to give a residue.The residue was slurried in PE/EA=20:1 (200 mL) and filtered to give thetitle compound (107 g, 87% yield) as yellow solid. MS (ES+) C₁₀H₉NO₃requires: 191, found: 192[M+H]⁺.

Step 2: 1,3-Dichloro-8-methoxyisoquinoline

To a solution of(E)-2-(hydroxyimino)-7-methoxy-2,3-dihydro-1H-inden-1-one (107 g, 522mmol, 1.00 eq) in dioxane (500 mL) was added POCl₃ (126 g, 827 mmol,76.9 mL, 1.59 eq) and HCl (4 M in dioxane, 1.31 mL, 0.01 eq) at 0-10° C.The reaction mixture was stirred at 70° C. for 12 h, then was cooled to25° C. and quenched with water (2.00 L). The quenched mixture wasextracted with DCM (500 mL×4) and the organic layers were washed withbrine (500 mL×2), dried over Na₂SO₄, filtered and concentrated to give aresidue. The residue was purified by column chromatography (SiO₂,PE/EA=20/1 to 10/1) to give the title compound (48.8 g, 40.9% yield) aslight yellow solid. MS (ES+) C₁₀H₇C₁₂NO requires: 227, found: 228[M+H]⁺.

Step 3: 3-Chloro-8-methoxyisoquinoline

To a solution of 1,3-dichloro-8-methoxyisoquinoline (48.8 g, 213 mmol,1.00 eq) in THE (250 mL) was added TMEDA (37.3 g, 320 mmol, 48.4 mL,1.50 eq) and Pd(dppf)Cl₂ (1.57 g, 2.14 mmol, 0.01 eq) at 25° C. ThenNaBH₄ (17.2 g, 456 mmol, 2.13 eq) was slowly added to the reactionmixture and the reaction mixture was stirred at 25° C. for 1 h. Thereaction mixture was poured into 1N HCl (1.00 L), extracted with EA (200mL×3). The combined organic layers were filtered through Celite® and thefiltrate was washed with brine (500 mL), dried over Na₂SO₄, filtered andconcentrated to give a residue. The residue was purified by columnchromatography (SiO₂, PE/EA=20/1 to 5/1) to give the title compound(26.7 g, 64.3% yield) as a light yellow solid. MS (ES+) C₁₀H₃ClNOrequires: 193, found: 194[M+H]⁺.

Step 4: 5-Bromo-3-chloro-8-methoxyisoquinoline

To a solution of 3-chloro-8-methoxyisoquinoline (26.7 g, 137 mmol, 1.00eq) in MeCN (300 mL) was added NBS (29.3 g, 165 mmol, 1.20 eq) at 25° C.The reaction mixture was stirred at 70° C. for 1 h, then was cooled to25° C. The mixture was filtered and the filter cake was washed with MeCN(100 mL). The filter cake was collected and dried under vacuum. Thefiltrate was purified by column chromatography (SiO₂, PE/EA=1:0 to 1:1,Rf=0.45) to give the title compound (26.17 g, 69.6% yield) as anoff-white solid. MS (ES+) C₁₀H₇BrClNO requires: 273, found: 274[M+H]⁺.

Step 5: 3-Chloro-8-methoxy-5-vinylisoquinoline

To a mixture of 5-bromo-3-chloro-8-methoxyisoquinoline (1.00 g, 3.67mmol), potassium vinyltrifluoroborate (688 mg, 5.14 mmol) in EtOH (20.0mL) and water (2.00 mL) was added TEA (743 mg, 7.34 mmol, 1.02 mL) andPd(dppf)Cl₂.CH₂Cl₂ (300 mg, 367 μmol), then the mixture was stirred at80° C. for 1 h. The reaction mixture was then concentrated to give aresidue. The residue was diluted with water (30.mL) and extracted withEA (20 ml×3). The combined organic layers were dried over anhydroussodium sulfate, filtered and concentrated to give a residue. The residuewas purified by column chromatography (SiO₂, PE/EA=1/0 to 10/1) to givethe title compound (620 mg, 2.82 mmol, 77% yield) as a yellow solid. MS(ES+) C₁₂H₁₀ClNO requires: 219, found: 220[M+H]⁺.

Steps 6-8:(S)—N—((S)-1-(3-Chloro-8-methoxyisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamideand(S)—N—((R)-1-(3-chloro-8-methoxyisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamide

The title compounds were prepared from3-chloro-8-methoxy-5-vinylisoquinoline using a similar procedure asdescribed in Steps 5-7 for Intermediates 71 and 72. The mixture ofdiastereomers was separated by prep-HPLC (column: Welch Xtimate C18150*30 mm*5 um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN];B %: 32%-62%, 11.5 min) to give the title compounds separately. Thestereochemistry at the ethyl amine stereocenter was arbitrarilyassigned.

Peak 1 (Intermediate 73):(S)—N—((S)-1-(3-Chloro-8-methoxyisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamideor(S)—N—((R)-1-(3-chloro-8-methoxyisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamide(15.0 mg, 17% yield) as a yellow oil. MS (ES+) C₁₇H₂₃ClN₂O₂S requires:354, found: 355[M+H]⁺.Peak 2 (Intermediate 74):(S)—N—((S)-1-(3-Chloro-8-methoxyisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamideor(S)—N—((R)-1-(3-chloro-8-methoxyisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamide(15.0 mg, 17% yield) as a yellow oil. MS (ES+) C₁₇H₂₃ClN₂O₂S requires:354, found: 355[M+H]⁺.

Intermediates 75 and 76:(S)—N—((S)-1-(6-Chloro-1-methoxy-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamideand(S)—N—((R)-1-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide

Step 1: 6-Chloro-1-methoxy-2,7-naphthyridine-4-carbaldehyde OsO₄ (4% inwater, 0.576 mL, 0.113 mmol) was added to a mixture of6-chloro-1-methoxy-4-vinyl-2,7-naphthyridine (Step 1, Intermediate 71)(1 g, 4.54 mmol), 2,6-lutidine (0.528 mL, 4.53 mmol), NaIO₄ (0.969 g,4.53 mmol) in dioxane (34 mL) and water (11 mL). The reaction mixturewas stirred at 25° C. for 2 h, then was partitioned between DCM andwater. The organic layer was dried over sodium sulfate, filtered, andconcentrated to give a residue. The residue was purified by columnchromatography (SiO₂, PE:EA=1/0 to 0/1) to give the title compound (360mg) as a yellow solid.

Steps 2-3:(S)—N—((S)-1-(6-Chloro-1-methoxy-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamideand(S)—N—((R)-1-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide

The title compounds were prepared from6-chloro-1-methoxy-2,7-naphthyridine-4-carbaldehyde using a similarprocedure as described in Steps 6-7 of Intermediate 71. The mixture ofdiastereomers was separated by SFC (column: Chiralpak IC-H 21×250 mm;mobile phase: MeOH in CO₂) to give the title compounds separately. Thestereochemistry at the ethyl amine stereocenter was arbitrarilyassigned.

Peak 1 (Intermediate 75):(S)—N—((S)-1-(6-Chloro-1-methoxy-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamideor(S)—N—((R)-1-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(70 mg) as a yellow oil. MS (ES+) C₁₆H₂₂ClN₃O₂S requires: 355, found:356[M+H]⁺.Peak 2 (Intermediate 76):(S)—N—((S)-1-(6-Chloro-1-methoxy-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamideor(S)—N—((R)-1-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(73 mg) as a yellow oil. MS (ES+) C₁₆H₂₂ClN₃O₂S requires: 355, found:356[M+H]⁺.

Intermediates 77 and 78:(R)—N—((S)-1-(3,8-Dichloroisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamideand(R)—N—((R)-1-(3,8-dichloroisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamide

Step 1: 5-Bromo-3,8-dichloroisoquinoline

To a solution of 5-bromo-8-chloro-isoquinolin-3-amine (2 g, 7.77 mmol, 1eq) and benzyl(triethyl)ammonium chloride (3.54 g, 15.53 mmol, 2 eq) inDCM (20 mL) was added 1-BuONO (3.20 g, 31.07 mmol, 3.69 mL, 4 eq) at 0°C. The mixture was stirred at 30° C. for 12 h, then was poured intosaturated aqueous NaHCO₃ solution (100 mL) and extracted with EA (50mL×3). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated to give a residue. The residue was purified by columnchromatography (SiO₂, PE/EA=50/1 to 5/1) to give the title compound (1.1g, 3.97 mmol, 51.14% yield) as a yellow solid.

Steps 2-5:(R)—N—((S)-1-(3,8-Dichloroisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamideand(R)—N—((R)-1-(3,8-dichloroisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamide

The title compounds were prepared from 5-bromo-3,8-dichloroisoquinolineusing a similar procedure as described in Step 1 of Example 13, Step 1of Intermediate 75, and Steps 6-7 of Intermediate 71. The mixture ofdiastereomers was separated by column chromatography (SiO₂, Petroleumether/Ethyl acetate=10/1 to 1/2) followed by prep-TLC (SiO₂, Petroleumether/Ethyl acetate=1/2) to give the title compounds separately. Thestereochemistry at the ethyl amine stereocenter was arbitrarilyassigned.

Peak 1 (Intermediate 77):(R)—N—((S)-1-(3,8-Dichloroisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamideand(R)—N—((R)-1-(3,8-dichloroisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamide(35 mg, 21% yield) as a yellow solid. MS (ES+) C₁₆H₂₀Cl₂N₂OS requires:358, found: 359[M+H]⁺.Peak 2 (Intermediate 78):(R)—N—((S)-1-(3,8-Dichloroisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamideand(R)—N—((R)-1-(3,8-dichloroisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamide(35 mg, 19% yield) as a yellow solid. MS (ES+) C₁₆H₂₀Cl₂N₂OS requires:358, found: 359[M+H]⁺.

Intermediates 79 and 80:(S)—N—((S)-1-(6-Chloro-1-(1-methylcyclopropoxy)-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamideand(S)—N—((R)-1-(6-chloro-1-(1-methylcyclopropoxy)-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide

The title compounds were prepared from(S,E)-N-((6-chloro-1-(1-methylcyclopropoxy)-2,7-naphthyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide(which was prepared from 4-bromo-1,6-dichloro-2,7-naphthyridine(Intermediates 33 and 34) using similar procedures as described abovefor Intermediate 75) using a similar procedure as described in Step 7 ofIntermediate 71. The mixture of diastereomers was separated by prep-TLC(petroleum ether: ethyl acetate=1:1) to give the title compoundsseparately. The stereochemistry at the ethyl amine stereocenter wasarbitrarily assigned.

Peak 1 (Intermediate 79):(S)—N—((S)-1-(6-Chloro-1-(1-methylcyclopropoxy)-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamideor(S)—N—((R)-1-(6-chloro-1-(1-methylcyclopropoxy)-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(20 mg, 36% yield) as a yellow solid. MS (ES+) C₁₉H₂₆ClN₃O₂S requires:395, found: 396[M+H]⁺.

Peak 2 (Intermediate 80):(S)—N—((S)-1-(6-Chloro-1-(1-methylcyclopropoxy)-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamideor(S)—N—((R)-1-(6-chloro-1-(1-methylcyclopropoxy)-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide(20 mg, 41% yield) as a white solid. MS (ES+) C₁₉H₂₆ClN₃O₂S requires:395, found 396[M+H]⁺.

Intermediate 81 and 82:(S)-4-(1-Azido-2-methoxyethyl)-6-chloro-1-methoxy-2,7-naphthyridine and(R)-4-(1-azido-2-methoxyethyl)-6-chloro-1-methoxy-2,7-naphthyridine

Steps 1-3:(S)-4-(1-Azido-2-methoxyethyl)-6-chloro-1-methoxy-2,7-naphthyridine or(R)-4-(1-azido-2-methoxyethyl)-6-chloro-1-methoxy-2,7-naphthyridine

The title compound was prepared from6-chloro-1-methoxy-4-vinyl-2,7-naphthyridine (Step 1, Intermediate 71)using a similar procedure as described in Steps 2-4 of Intermediate 67,except that after Step 2 the dimethoxy intermediate was isolated andused in Step 3. The racemic mixture (6.5 g, 22.1 mmol) was separated bychiral-SFC (column: Daicel Chiralpak AD (250 mm×50 mm, 10 um); mobilephase: [0.1% NH₃H₂O-MeOH]) to give(S)-4-(1-azido-2-methoxyethyl)-6-chloro-1-methoxy-2,7-naphthyridine or(R)-4-(1-azido-2-methoxyethyl)-6-chloro-1-methoxy-2,7-naphthyridine(Intermediate 81, first eluting isomer, 3.2 g, 45% yield) as white solidand (S)-4-(1-azido-2-methoxyethyl)-6-chloro-1-methoxy-2,7-naphthyridineor (R)-4-(1-azido-2-methoxyethyl)-6-chloro-1-methoxy-2,7-naphthyridine(Intermediate 82, second eluting isomer, 3 g, 46% yield) as a whitesolid. ¹H NMR (400 MHz, CDCl₃): δ ppm 9.43 (s, 1H), 8.25 (s, 1H), 7.86(s, 1H), 5.03-4.99 (m, 1H), 4.18 (s, 3H), 3.84-3.79 (m, 1H), 3.78-3.74(m, 1H), 3.45 (s, 3H).

Intermediate 83: 5-Amino-3-(2-fluoropropan-2-yl)pyrazine-2-carbonitrile

Steps 1-6: 5-Amino-3-(2-fluoropropan-2-yl)pyrazine-2-carbonitrile

The title compound was prepared from 2,6-dibromopyrazine using the samesix-step procedure as described in Step 1 of Intermediate 26(substituting acetone instead of propionaldehyde) and Steps 1-5 ofIntermediate 23. MS (ES+) C₈H₉FN₄ requires: 180, found: 181 [M+H]⁺.

Intermediate 84: 6-Chloro-4-iodo-1-methoxy-2,7-naphthyridine

Step 1: 6-Chloro-4-iodo-2,7-naphthyridin-1(2H)-one

NIS (1.31 g, 5.81 mmol) was added to a solution of6-chloro-2,7-naphthyridin-1(2H)-one (1.00 g, 5.54 mmol) in AcOH (20 mL).The reaction mixture was stirred at 23° C. for 60 h, then the aceticacid was removed in vacuo. The residue was treated with saturatedaqueous NaHCO₃ solution, stirred for 1 h, then filtered. The filter cakewas washed with water and dried under vacuum to give the title compound(1.52 g, 90%) as an off-white solid. MS (ES+) C₉H₄ClIN₂O requires: 306,found: 307[M+H]⁺.

Steps 2-3: 6-Chloro-4-iodo-1-methoxy-2,7-naphthyridine

The title compound was prepared from6-chloro-4-iodo-2,7-naphthyridin-1(2H)-one using the same two-stepprocedure described in Steps 2-3 of Intermediate 31. MS (ES+) C₉H₆ClIN₂Orequires: 320, found: 321 [M+H]⁺.

Intermediate 85:2′-Amino-7′,7′-dimethyl-5′H,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridin]-5′-one

Step 1: 2-(1-(3-Bromo-6-chloropyridin-2-yl)cyclopropyl)propan-2-ol

To a solution of methyl1-(3-bromo-6-chloropyridin-2-yl)cyclopropane-1-carboxylate (1.3 g, 4.47mmol) in THE (10 mL) was added MeMgBr (3 M, 14.9 mL) at 25° C. Thereaction mixture was stirred at 25° C. for 10 min, then was poured intowater (20 mL) and extracted with EA (50 mL×3). The organic layers werecombined and dried over sodium sulfate, filtered, and concentrated togive a residue. The residue was purified by column chromatography (SiO₂,PE/EA=1/0 to 50/1) to give the title compound (500 mg, 38% yield) ascolorless oil.

Steps 2-5:2′-Amino-7′,7′-dimethyl-5′H,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridin]-5′-one

The title compound was prepared from2-(1-(3-Bromo-6-chloropyridin-2-yl)cyclopropyl)propan-2-ol using asimilar procedure as described in Steps 4-6 for Intermediate 45 and Step7 of Intermediate 50 above. ¹H NMR (400 MHz, CDCl₃): δ ppm 8.05 (d,J=8.4 Hz, 1H), 6.36 (d, J=8.8 Hz, 1H), 4.85 (s, 2H), 1.42-1.32 (m, 8H),1.06-1.03 (m, 2H).

Example 1:5-(1-Aminoethyl)-N-(2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-8-methoxy-2,7-naphthyridin-3-amine(1)

Step 1: 1-(6-Chloro-1-methoxy-2,7-naphthyridin-4-yl)ethan-1-ol

Sodium borohydride (120 mg, 3.17 mmol) was added to a solution of1-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)ethan-1-one (500 mg, 2.11mmol) in methanol (10 mL) and the mixture was stirred at 25° C. for 10minutes. The reaction was quenched by addition of water (5 mL) andextracted with EA (5 mL×3). The combined organic layers wereconcentrated under reduced pressure to give a residue. The residue waspurified by flash-column chromatography to give the title compound (400mg, 79% yield) as an off-white solid.

Step 2:1-(6-((2-(2-Fluoropropan-2-yl)pyrimidin-4-yl)amino)-1-methoxy-2,7-naphthyridin-4-yl)ethan-1-ol

2-(Dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl(BrettPhos) (90.0 mg, 168 umol) and BrettPhos Pd G4 (154.28 mg, 167.60umol) were added to a mixture of1-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)ethan-1-ol (400 mg, 1.68mmol), 2-(2-fluoropropan-2-yl)pyrimidin-4-amine (Intermediate 1, 312 mg,2.01 mmol) and potassium acetate (822 mg, 8.38 mmol) in dioxane (20 mL).The solution was degassed and purged with N₂ for 3 times, and themixture was stirred at 100° C. for 1 h under N₂ atmosphere. The reactionmixture was quenched by addition of water (30 mL) and extracted with EA(30 mL×3). The combined organic layers were washed with water (60 mL×3)and concentrated under reduced pressure to give a residue. The residuewas purified by flash-column chromatography and reverse phase prep-HPLCto give the title compound (280 mg, 45% yield) as a white solid. MS(ES+) C₁₄H₂₀FN₅O₂ requires 357, found 358 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 10.70 (s, 1H), 9.31 (s, 1H), 8.94-8.76 (m, 1H), 8.48 (d,J=5.6 Hz, 1H), 8.17 (s, 1H), 8.07 (d, J=5.6 Hz, 1H), 7.25 (d, J=5.6 Hz,1H), 5.28-5.18 (m, 1H), 4.11-4.03 (m, 3H), 1.82 (d, J=2.4 Hz, 3H), 1.76(d, J=2.4 Hz, 3H), 1.50 (d, J=6.4 Hz, 3H).

Step 3:5-(1-Azidoethyl)-N-(2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-8-methoxy-2,7-naphthyridin-3-amine

Trimethylsilylazide (116 mg, 1.01 mmol) and indium bromide (238 mg, 672umol) were added under an atmosphere of nitrogen to a solution of1-(6-((2-(2-fluoropropan-2-yl)pyrimidin-4-yl)amino)-1-methoxy-2,7-naphthyridin-4-yl)ethan-1-ol(120 mg, 336 umol) in dichloromethane (10 mL). The mixture was stirredat 25° C. for 6 h. TLC showed starting material was consumed and a newspot was detected. The reaction mixture was poured into water (20 mL),and extracted with EA (20 mL×3). The combined organic layers wereconcentrated under reduced pressure to give a residue. The residue waspurified by prep-TLC [petroleum ether:EA=1:1] to give the title compound(80 mg, 61% yield) as a white solid. MS (ES+) C₁₈H₁₉FN₈O requires 382,found 383 [M+H]⁺

Step 4:5-(1-Aminoethyl)-N-(2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-8-methoxy-2,7-naphthyridin-3-amine

Pd/C (10.0 mg, 78.5 umol, 10% purity) was added under N₂. to a solutionof5-(1-Azidoethyl)-N-(2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-8-methoxy-2,7-naphthyridin-3-amine(50 mg, 131 umol) in methanol (10 mL). The suspension was degassed undervacuum and purged with H₂ several times. The mixture was stirred underH₂ (15 psi) at 25° C. for 4 h. The reaction mixture was filtered andconcentrated under reduced pressure to remove solvent. The residue wasdiluted with EA (10 mL) and extracted with water (10 mL×3). The combinedorganic layers were washed with EA (5 mL×3) and concentrated underreduced pressure to give a residue. The residue was combined with aprevious batch (20 mg). The combined residue was purified by reversephase prep-HPLC (column: Phenomenex Gemini 150×25 mm×10 um; mobilephase: [water (10 mM NHsHCO₃)-MECN]; B %: 30%-51%, 7 min) to give thetitle compound (45 mg, 60% yield) as a white solid. MS (ES+) C₁₈H₂₁FN₆Orequires 356, found 357 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ ppm9.59-9.46 (m, 1H), 8.86 (s, 1H), 8.04 (s, 1H).

Step 5: (R orS)-5-(1-Aminoethyl)-N-(2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-8-methoxy-2,7-naphthyridin-3-amine

5-(1-aminoethyl)-N-(2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-8-methoxy-2,7-naphthyridin-3-amine(60 mg, 168 umol) was separated by SFC (column: DAICEL CHIRALPAK AS (250mm×30 mm, 10 um); mobile phase: [0.1% NH₃H₂O MeOH]; B %: 30MeOH (NH₄OH)%-30MeOH (NH₄OH) %, 5.0 min; 65 min) to give the 2 isomers (firsteluting isomer (12.9 mg, 26% yield) and second eluting isomer (13.7 mg,29% yield)) as brown solids (stereochemistry arbritrarily assigned).Spectra analysis of isomer 1: MS (ES+) C₁₈H₂₁FN₆O requires 356, found357 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ ppm 9.33 (s, 1H), 8.83 (s, 1H),8.41 (d, J=6.0 Hz, 1H), 8.20 (s, 1H), 7.20 (d, J=6.0 Hz, 1H), 4.70 (q,J=6.8 Hz, 1H), 4.13 (s, 3H), 1.87 (d, J=2.0 Hz, 3H), 1.81 (d, J=2.0 Hz,3H), 1.59 (d, J=6.8 Hz, 3H). Spectra analysis of isomer 2: MS (ES+)C₁₈H₂₁FN₆O requires 356, found 357 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δppm 9.23 (s, 1H), 8.74 (s, 1H), 8.30 (br s, 1H), 8.09 (d, J=3.2 Hz, 1H),7.08 (s, 1H), 4.60 (s, 1H), 4.02 (d, J=4.0 Hz, 3H), 1.84-1.61 (m, 6H),1.49 (s, 3H), 1.19 (s, 1H).

Example 2:5-(2-Aminopropan-2-yl)-N-(2-(tert-butyl)pyrimidin-4-yl)-8-methoxy-2,7-naphthyridin-3-amine(3)

Step 1:2-(6-((2-(Tert-butyl)pyrimidin-4-yl)amino)-1-methoxy-2,7-naphthyridin-4-yl)propan-2-ol

2-(Dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl(BrettPhos) (40.0 mg, 75.2 umol) and BrettPhos Pd G4 (69.0 mg, 75.2umol) were added to a mixture of2-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)propan-2-ol (Intermediate31, 190 mg, 752 umol), 2-(tert-butyl)pyrimidin-4-amine (125 mg, 827umol) and potassium acetate (221 mg, 2.26 mmol) in dioxane (3 mL). Thesolution was degassed and purged with N₂ for 3 times, and then themixture was stirred at 100° C. for 1 hour under N₂ atmosphere. LCMSshowed desired mass was detected and starting material was consumed. Thereaction mixture was concentrated and the residue was purified byreverse phase prep-HPLC (column: Phenomenex Gemini 150×25 mm×10 um;mobile phase: [water (10 mM NH₄HCO₃)-MeCN]; B %: 50%-71%, 7 min) to givethe title compound (106.9 mg, 39% yield) as a white solid. MS (ES+)C₂₀H₂₅N₅O₂ requires 367, found 368 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δppm 9.36 (s, 1H), 8.76 (s, 1H), 8.31 (d, J=6.0 Hz, 1H), 8.14 (s, 1H),7.40 (d, J=6.0 Hz, 1H), 4.12 (s, 3H), 1.79 (s, 6H), 1.45 (s, 9H).

Step 2:5-(2-Azidopropan-2-yl)-N-(2-(tert-butyl)pyrimidin-4-yl)-8-methoxy-2,7-naphthyridin-3-amine

Indium bromide (183 mg, 517 umol) and trimethylsilylazide (33.0 mg, 284umol, 37 uL) were added to a solution of2-(6-((2-(tert-butyl)pyrimidin-4-yl)amino)-1-methoxy-2,7-naphthyridin-4-yl)propan-2-ol(95.0 mg, 259 umol) in dichloromethane (8 mL) under N₂. The mixture wasstirred at 25° C. for 16 h. LCMS showed desired mass was detected andstarting material was consumed. The reaction mixture was diluted withwater (15 mL) and extracted with dichloromethane (15 mL×3). The combinedorganic layers were dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to give the title compound (100 mg,99% yield) as a yellow solid which was used for next step withoutfurther purification. MS (ES+) C₂₀H₂₄N₈O requires 392, found 393 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): δ ppm 9.43 (s, 1H), 8.67 (s, 1H), 8.48 (d,J=5.6 Hz, 1H), 8.14 (s, 1H), 7.21-7.12 (m, 1H), 4.16 (s, 3H), 1.84 (s,6H), 1.50 (s, 9H).

Step 3:5-(2-Aminopropan-2-yl)-N-(2-(tert-butyl)pyrimidin-4-yl)-8-methoxy-2,7-naphthyridin-3-amine

Pd/C (40.0 mg, 10% purity) was added to a solution of5-(2-Azidopropan-2-yl)-N-(2-(tert-butyl)pyrimidin-4-yl)-8-methoxy-2,7-naphthyridin-3-amine(80.0 mg, 204 umol) in methanol (8 mL) under N₂. The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (15 psi) at 25° C. for 16 h. LCMS showed desired masswas detected and starting material was consumed. The reaction mixturewas filtered and concentrated. The residue was purified by reverse phaseprep-HPLC (column: Phenomenex Gemini 150×25 mm×10 um; mobile phase:[water (10 mM NH₄OAc)-MECN]; B %: 20%-71%, 7 min) followed by prep-TLCto give the title compound (31.5 mg, 42% yield) as a white solid. MS(ES+) C₂₀H₂₆N₆O requires 366, found 367 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD):δ ppm 9.39 (s, 1H), 8.58 (s, 1H), 8.34 (d, J=5.6 Hz, 1H), 8.19 (s, 1H),7.47 (d, J=6.0 Hz, 1H), 4.12 (s, 3H), 1.76 (s, 6H), 1.45 (s, 9H).

Example 3a:5-(2-Aminopropan-2-yl)-N-(2-(tert-butyl)pyrimidin-4-yl)-8-methoxy-2,7-naphthyridin-3-amine(34)

Step 1:2-((5-(2-Azidopropan-2-yl)-8-methoxy-2,7-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one

2-(Dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl(BrettPhos) (30.9 mg, 57.6 μmol) and BrettPhos Pd G4 (26.5 mg, 28.8μmol) were added to a mixture of2-amino-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one (Intermediate 9, 80.0mg, 288 μmol),4-(2-azidopropan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine(Intermediate 31a, 56.0 mg, 294 μmol) and potassium acetate (84.8 mg,864 μmol) in dioxane (2 mL). The solution was degassed and purged withnitrogen atmosphere for 3 times, and then the mixture was stirred at100° C. for 1 hour under nitrogen atmosphere. LCMS showed desired masswas detected and starting material was consumed. The reaction mixturewas concentrated under reduced pressure to give a residue. The residuewas purified by flash-column chromatography to give the title compound(120 mg, 78% yield) as a white solid. MS (ES+) C₂₃H₂₅N₇O₂ requires 431,found 432 [M+H]⁺.

Step 2:2-((5-(2-Aminopropan-2-yl)-8-methoxy-2,7-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one

Pd/C (232 μmol, 10% purity) was added to a solution of2-((5-(2-azidopropan-2-yl)-8-methoxy-2,7-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one(100 mg, 232 μmol) in methanol (2 mL) under H₂. The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (15 psi) at 25° C. for 1 hour. The reaction mixture wasfiltered and concentrated under reduced pressure to give a residue. Theresidue was purified by reverse phase prep-HPLC (column: Phenomenex lunaC18 150×25 mm×10 um; mobile phase: [water (10 mM NH₄HCO₃)-MeCN]; B %:30%-60%, 10 min) to give the title compound (4.80 mg, 4.9% yield) as awhite solid. MS (ES+) C₂₃H₂₇N₅O₂ requires 405, found 406 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD): δ ppm 9.47 (s, 1H), 9.33 (s, 1H), 8.19 (s, 1H), 8.11(d, J=8.8 Hz, 1H), 7.09 (d, J=8.8 Hz, 1H), 4.12 (s, 3H), 3.04 (s, 2H),2.53 (s, 2H), 1.84 (s, 6H), 1.14 (s, 6H).

Example 3b:R-2-((5-(1-amino-1-cyclopropylethyl)-8-cyclopropoxy-2,7-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(74)

each of which is represented by one of the structures shown below:

Step 1:1-(6-Chloro-1-cyclopropoxy-2,7-naphthyridin-4-yl)-1-cyclopropylethan-1-ol

Cyclopropylmagnesium bromide (3 M, 3.17 mL) was added to a solution of1-(6-chloro-1-cyclopropoxy-2,7-naphthyridin-4-yl)ethan-1-one (500 mg,1.90 mmol) in methyl tert butyl ether (8 mL) at 15° C. under nitrogenatmosphere. The mixture was stirred for 1 h at 60° C. LCMS showeddesired mass was detected and starting material was consumed. Thereaction mixture was quenched by the addition of saturated aqueousammonium chloride (20 mL), followed by addition of water (20 mL) andextracted with EA (30 mL×3). The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to give a residue. The residue was purified by flash-columnchromatography to give the title compound (460 mg, 72% yield) as a whitesolid. MS (ES+) C₁₆H₁₇ClN₂O₂ requires 304, found 305 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): δ ppm 9.32-9.28 (m, 1H), 8.59 (d, J=0.8 Hz, 1H), 8.54-8.50(m, 1H), 4.56-4.48 (m, 1H), 2.43-2.21 (m, 1H), 1.58 (d, J=0.8 Hz, 1H),1.57-1.48 (m, 2H), 0.73-0.50 (m, 6H).

Step 2:4-(1-Azido-1-cyclopropylethyl)-6-chloro-1-cyclopropoxy-2,7-naphthyridine

BF₃.Et₂O (382 mg, 2.69 mmol) was added to a solution of1-(6-chloro-1-cyclopropoxy-2,7-naphthyridin-4-yl)-1-cyclopropylethan-1-ol(410 mg, 1.35 mmol) and TMSN₃ (155 mg, 1.35 mmol) in dichloromethane (8mL) under nitrogen atmosphere. The reaction mixture was stirred at 25°C. for 0.5 h. LCMS showed desired mass was detected and startingmaterial was consumed. The reaction mixture was diluted with water (30mL) and was extracted with EA (30 mL×3). The combined organic layerswere dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to give a residue. The residue was purified byflash-column chromatography to give the title compound (225 mg, 48%yield) as a colorless oil. MS (ES+) C₁₆H₁₆ClN₅O requires 329, found 330[M+H]⁺.

Step 3:(R)-4-(1-azido-1-cyclopropylethyl)-6-chloro-1-cyclopropoxy-2,7-naphthyridineand(S)-4-(1-azido-1-cyclopropylethyl)-6-chloro-1-cyclopropoxy-2,7-naphthyridine

4-(1-Azido-1-cyclopropylethyl)-6-chloro-1-cyclopropoxy-2,7-naphthyridine(225 mg) was separated by SFC (column: DAICEL CHIRALPAK AD-H (250 mm×30mm, 5 μm); mobile phase: [0.1% NH₃H₂O EtOH]; B %: 25%-25%, 4 min; 180min). The title compounds (35 mg, 16% yield; first eluting isomer((S)-4-(1-azido-1-cyclopropylethyl)-6-chloro-1-cyclopropoxy-2,7-naphthyridine))and (50 mg, 22% yield; second eluting isomer((R)-4-(1-azido-1-cyclopropylethyl)-6-chloro-1-cyclopropoxy-2,7-naphthyridine))were obtained as white solids. The stereochemistry of the isomers wereassigned based on an X-ray crystal structure of compound 75. MS (ES+)C₁₆H₁₆ClN₅O requires 329, found 330 [M+H]⁺.

Step 4:R-2-((5-(1-azido-1-cyclopropylethyl)-8-cyclopropoxy-2,7-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

2-(Dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl(BrettPhos) (11.4 mg, 21.2 umol) and BrettPhos Pd G4 (9.77 mg, 10.6umol) were added to a mixture of2-amino-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(Intermediate 2, 22.4 mg, 117 umol),R-4-(1-azido-1-cyclopropylethyl)-6-chloro-1-cyclopropoxy-2,7-naphthyridine(second eluting isomer from step 3, 35 mg, 106 umol) and potassiumacetate (31.3 mg, 318 umol) in dioxane (4 mL). The mixture was degassedand purged with nitrogen atmosphere for 3 times, and then stirred at 60°C. for 1 h under nitrogen atmosphere. LCMS showed desired mass wasdetected and starting material was consumed. The reaction mixture wasfiltered and concentrated under reduced pressure to give a residue. Theresidue was purified by prep-TLC to give the title compound (50 mg, 93%yield) as a yellow solid. MS (ES+) C₂₆H₂₇N₇O₃ requires 485, found 486[M+H]⁺.

Step 5:R-2-((5-(1-amino-1-cyclopropylethyl)-8-cyclopropoxy-2,7-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

Zn (23.6 mg, 360 umol) and acetic acid (43.3 mg, 721 umol) were added toa solution ofR-2-((5-(1-azido-1-cyclopropylethyl)-8-cyclopropoxy-2,7-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(35 mg, 72.1 umol) from Step 4 in tetrahydrofuran (6 mL) and the mixturewas stirred at 25° C. for 0.5 h. LCMS showed desired mass was detectedand starting material was consumed. The reaction mixture was filtered,concentrated in vacuo to give the residue. The residue was purified byreverse phase prep-HPLC to give the title compound (13.4 mg, 39% yield)as a yellow solid. MS (ES+) C₂₆H₂₉N₅O₃ requires 459, found 460 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): δ ppm 9.27 (s, 1H), 9.19 (s, 1H), 8.52 (s, 1H),8.15-8.11 (m, 2H), 7.24 (d, J=8.8 Hz, 1H), 4.54-4.46 (m, 1H), 3.18 (d,J=0.8 Hz, 2H), 1.84 (s, 3H), 1.65-1.56 (m, 1H), 1.52 (d, J=7.6 Hz, 6H),0.94-0.86 (m, 4H), 0.84-0.67 (m, 3H), 0.65-0.54 (m, 1H).

Example 4:5-(2-Aminopropan-2-yl)-N-(2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-8-methoxyisoquinolin-3-amine(5)

Step 1: Methyl 2,2-diethoxyacetimidate

2,2-diethoxyMeCN (8.4 g, 65 mmol, 9 mL) was added to a solution of Na(149.5 mg, 6.5 mmol, 154.1 uL) in MeOH (70 mL). The mixture was stirredat 25° C. for 12 h. The reaction mixture was filtered and concentratedunder reduced pressure to give a residue. The residue was filtered,washed with Petroleum ether:MeOH (2:1; 3 times), and then the filtratewas concentrated under reduced pressure to give the title compound (10g, crude) as a white oil.

Step 2: N-(5-bromo-2-methoxybenzyl)-2,2-diethoxyacetimidamide

Methyl 2,2-diethoxyethanimidate (8.9 g, 55.5 mmol) was added to asolution of (5-bromo-2-methoxy-phenyl)methanamine (10 g, 46.3 mmol) inMeOH (100 mL) under an atmosphere of N₂. The mixture was stirred at 25°C. for 12 h. LCMS showed desired MS was detected. The reaction mixturewas filtered and concentrated under reduced pressure to give a residue.The residue was diluted with H₂O (50 mL) and extracted with DCM 200 mL(50 mL×4). The combined organic layers were washed with saturatedaqueous NaCl solution (50 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the title compound (12 g,crude) as a white solid which was used in the next step without furtherpurification.

Step 3: 5-Bromo-8-methoxyisoquinolin-3-amine

N-(5-bromo-2-methoxybenzyl)-2,2-diethoxyacetimidamide (11 g, 31.9 mmol)was added to H₂SO₄ (111.61 g, 1.1 mol, 60.6 mL, 98% purity) at 0° C.,and then the mixture was stirred at 25° C. for 3 h under an atmosphereof N₂. The reaction mixture was quenched by addition of NaOH (120 g) inH₂O (5 L) at 0° C., and extracted with 2-MeTHF (1 L×2). The combinedorganic layers were washed with saturated aqueous NaCl solution (1 L),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The residue was purified by reverse phase prep-HPLC togive the title compound (3 g, 11.8 mmol, 37% yield) as a yellow solid.

Step 4: 5-(1-Ethoxyvinyl)-8-methoxyisoquinolin-3-amine

Pd(PPh₃)₄ (1.02 g, 884.8 μmol) and tributyl(1-ethoxyvinyl)stannane (6.79g, 18.8 mmol, 6.3 mL) were added to a solution of5-bromo-8-methoxyisoquinolin-3-amine (2.8 g, 11.1 mmol) in toluene (30mL) under N₂ atmosphere. The mixture was stirred at 100° C. for 4 hsunder N₂ atmosphere. The reaction mixture was quenched by addition ofaqueous CsF solution (60 mL) at 0° C. and extracted with EA (40 mL×3).The combined organic layers were washed with saturated aqueous NaClsolution (50 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give the title compound (2.7 g, crude) as a brownoil which was used in the next step without further purification.

Step 5: 1-(3-Amino-8-methoxyisoquinolin-5-yl)ethan-1-one

A mixture of 5-(1-ethoxyvinyl)-8-methoxyisoquinolin-3-amine (2.7 g, 11.1mmol) in THE (20 mL) and HCl (1M, 11 mL) was stirred at 25° C. for 30min under N₂ atmosphere. The reaction mixture was filtered to give thetitle compound (1.1 g, crude) as a yellow solid which was used in thenext step without further purification.

Step 6: 1-(3-Chloro-8-methoxyisoquinolin-5-yl)ethan-1-one

Pyridine hydrochloride (1.03 g, 8.9 mmol), CuCl (25.2 mg, 254.3 umol,6.08 uL) and NaNO₂ (614.2 mg, 8.9 mmol) were added to a solution of1-(3-amino-8-methoxyisoquinolin-5-yl)ethan-1-one (550 mg, 2.5 mmol) inDCM (5 mL) under N₂ atmosphere. HCl (37.6 mg, 381.5 umol, 36.9 uL, 37%purity) was then added to the reaction mixture at −10° C., and themixture was stirred at 0° C. for 30 min. The mixture was stirred at 25°C. for 1 h under N₂ atmosphere. The reaction mixture was filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by flash-column chromatography to give the title compound (530mg, 44% yield) as a white solid.

Step 7: 2-(3-Chloro-8-methoxyisoquinolin-5-yl)propan-2-ol

MeMgBr (3M in THF, 1.41 mL) was added to a solution of1-(3-Chloro-8-methoxyisoquinolin-5-yl)ethan-1-one (200 mg, 848.7 umol)in THF (2 mL) under N₂ atmosphere, and the reaction mixture was stirredat 25° C. for 1 h under N₂ atmosphere. The reaction mixture was quenchedby the addition of H₂O (10 mL) at 0° C. The reaction mixture wasfiltered and concentrated under reduced pressure to give a residue. Theresidue was purified by flash-column chromatography to give the titlecompound (580 mg, 90.5% yield) as a yellow solid.

Step 8:2-(3-((2-(2-Fluoropropan-2-yl)pyrimidin-4-yl)amino)-8-methoxyisoquinolin-5-yl)propan-2-ol

[2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (62.5 mg,79.5 umol) was added to a solution of2-(3-chloro-8-methoxyisoquinolin-5-yl)propan-2-ol (200 mg, 794.6 umol),Cs₂CO₃ (517.7 mg, 1.59 mmol) and2-(2-fluoropropan-2-yl)pyrimidin-4-amine (Intermediate 1, 135.6 mg, 874umol) in dioxane (2 mL) under N₂ atmosphere. The mixture was stirred at120° C. for 12 h under N₂ atmosphere. The reaction mixture was filteredand concentrated under reduced pressure to give a residue. The residuewas purified by flash-column chromatography to give the title compound(250 mg, 84% yield) as a yellow solid. ¹H-NMR (400 MHz, CD₃OD) δ ppm9.41 (s, 1H), 9.02 (s, 1H), 8.34 (d, 1H, J=6.0 Hz), 7.76 (d, 1H, J=8.0Hz), 7.33 (d, 1H, J=6.0 Hz), 6.84 (d, 1H, J=8.4 Hz), 4.05 (s, 3H), 1.84(t, 12H, J=9.2 Hz). MS (ES+) C₂₀H₂₃FN₄O₂ requires 370, found 371 [M+H]⁺.

Step 9:5-(2-Azidopropan-2-yl)-N-(2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-8-methoxyisoquinolin-3-amine

Indium tribromide (248.8 mg, 701.9 umol) and trimethylsilylazide (60.6mg, 526.4 umol, 69.2 uL) were added to a solution of2-(3-((2-(2-fluoropropan-2-yl)pyrimidin-4-yl)amino)-8-methoxyisoquinolin-5-yl)propan-2-ol(130 mg, 350.9 umol) under N₂ atmosphere in dichloromethane (2 mL). Themixture was stirred at 25° C. for 16 h. The reaction mixture wasconcentrated under reduced pressure and the residue was diluted with H₂O(5 mL) and extracted with EA (5 mL×3). The combined organic layers werewashed with saturated aqueous sodium chloride solution (5 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to givethe title compound (138 mg, crude) as a brown oil which was used in thenext without further purification.

Step 10:5-(2-aminopropan-2-yl)-N-(2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-8-methoxyisoquinolin-3-amine

Zn (228.2 mg, 3.5 mmol) and AcOH (0.2 mL) were added to a solution of5-(2-azidopropan-2-yl)-N-(2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-8-methoxyisoquinolin-3-amine(138 mg, 349 umol) in THE (2 mL) and IPA (0.4 mL). The mixture wasstirred at 25° C. for 3 h. The reaction mixture was filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by reverse phase prep-HPLC (column: Kromasil 150×25 mm×10 um;mobile phase: [water(0.04% NH₃H₂O+10 mM NH₄HCO₃)-MECN]; B %: 15%-45%, 10min) to give the title compound (64 mg, 49% yield) as a white solid.¹H-NMR (400 MHz, CD₃OD) δ ppm 9.42 (s, 1H), 9.03 (s, 1H), 8.35 (d, 1H,J=6.0 Hz), 7.76 (d, 1H, J=8.4 Hz), 7.28 (d, 1H, J=5.6 Hz), 6.85 (d, 1H,J=8.4 Hz), 4.05 (s, 3H), 1.80 (t, 13H, J=10.8 Hz). MS (ES+) C₂₀H₂₄FN₅Orequires 369, found 370 [M+H]⁺.

Example 5:4-(2-Aminopropan-2-yl)-N6-(2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-N1-methyl-2,7-naphthyridine-1,6-diamine(6)

Step 1:4-(2-Aminopropan-2-yl)-6-((2-(2-fluoropropan-2-yl)pyrimidin-4-yl)amino)-2,7-naphthyridin-1(2H)-one

HCl (1.5 M, 0.18 mL) was added to a solution of5-(2-aminopropan-2-yl)-N-(2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-8-methoxy-2,7-naphthyridin-3-amine(prepared similar to Example 3a, 20.0 mg, 54 umol) in tetrahydrofuran (2mL) and the solution was stirred at 25° C. for 16 h. The reactionmixture was basified by the addition of aqueous saturated sodiumbicarbonate solution (5 mL) followed by addition of water (15 mL) andthe mixture was extracted with EA (15 mL×3). The combined organic layerswere dried over anhydrous sodium sulfate, filtered and concentrated togive the title compound (19.0 mg, 99% yield) as a yellow solid which wasused for next step without further purification. MS (ES+) C₁₈H₂₁FN₆Orequires 356, found 357 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ ppm 9.30 (s,1H), 8.84 (s, 1H), 8.42 (d, J=6.0 Hz, 1H), 7.42 (d, J=6.0 Hz, 1H), 7.38(s, 1H), 1.81 (s, 3H), 1.75 (s, 3H), 1.70 (s, 6H).

Step 2:4-(2-Aminopropan-2-yl)-N6-(2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-N1-methyl-2,7-naphthyridine-1,6-diamine

DBU (6.0 mg, 42.1 umol, 6.3 uL) and BOP (19 mg, 42.1 umol) were added toa solution of methylamine (2 M in THF, 1 mL) in DMF (1 mL) followed byaddition of4-(2-aminopropan-2-yl)-6-((2-(2-fluoropropan-2-yl)pyrimidin-4-yl)amino)-2,7-naphthyridin-1(2H)-one(10.0 mg, 28.1 umol). The mixture was stirred at 25° C. for 16 h. Thereaction mixture was diluted with water (15 mL) and extracted with EA(15 mL×3). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified by reversephase prep-HPLC to give the title compound (3.4 mg, 32% yield) as ayellow solid. MS (ES+) C₁₉H₂₄FN₇ requires 369, found 370 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD): δ ppm 9.22 (s, 1H), 8.89 (s, 1H), 8.37 (d, J=6.0 Hz,1H), 8.04 (s, 1H), 7.32 (d, J=6.0 Hz, 1H), 3.05 (s, 3H), 1.81 (s, 3H),1.76 (s, 3H), 1.74 (s, 6H).

Example 6:5-((5-(2-Aminopropan-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)amino)-3-isopropylpyrazine-2-carbonitrile(8)

Step 1: 2-(6-Chloro-1-methoxy-2,7-naphthyridin-4-yl)propan-2-amine

Triphenyl phosphine (2.05 g, 7.83 mmol) was added to a solution of4-(2-azidopropan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine(Intermediate 31a, 870 mg, 3.13 mmol) in tetrahydrofuran (20 mL) andwater (5 mL) and then the mixture was stirred at 60° C. for 5 h. Thereaction mixture was diluted with water (15 mL) and extracted with EA(15 mL×3). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified byflash-column chromatography to give the title compound (1.7 g, crude) asa white solid.

¹H NMR (400 MHz, CDCl₃): δ ppm 9.24 (s, 1H), 9.07 (s, 1H), 7.75 (s, 1H),4.03 (s, 3H), 1.81 (s, 6H).

Step 2: 4-(2-Aminopropan-2-yl)-6-chloro-2,7-naphthyridin-1(2H)-one

HCl (3 M, 11 mL) was added to a solution of2-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)propan-2-amine (1.70 g, 6.75mmol) in tetrahydrofuran (15 mL) and the mixture was stirred at 25° C.for 16 h. The reaction mixture was diluted with water (15 mL) andextracted with EA (15 mL×3). The aqueous phase was basified by theaddition of saturated aqueous sodium bicarbonate solution (5 mL) andextracted with EA (15 mL×3). The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated to give the titlecompound (430 mg, 27% yield) as a yellow solid which was used for nextstep without further purification. ¹H NMR (400 MHz, CDCl₃): δ ppm 9.42(s, 1H), 9.12 (s, 1H), 8.7 (s, 1H), 1.72 (s, 6H).

Step 3: Tert-butyl(2-(6-chloro-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)propan-2-yl)carbamate

Triethylamine (128 mg, 1.26 mmol, 176 uL) was added to a solution of4-(2-aminopropan-2-yl)-6-chloro-2,7-naphthyridin-1(2H)-one (100 mg, 421umol) and (Boc)₂₀ (459 mg, 2.1 mmol, 483 uL) in dichloromethane (2 mL)and the mixture was stirred at 25° C. for 1 hour. The reaction mixturewas diluted with water (15 mL) and extracted with dichloromethane (15mL×3). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified by prep-TLC(silica, petroleum ether:EA=5:1) to give the title compound (20.0 mg,14% yield) as a yellow solid.

¹H NMR (400 MHz, CDCl₃): δ ppm 9.40 (s, 1H), 8.03 (s, 1H), 7.78 (s, 1H),4.98 (s, 1H), 1.70 (s, 6H), 1.65 (s, 9H).

Step 4: Tert-butyl(2-(6-chloro-1-(methylamino)-2,7-naphthyridin-4-yl)propan-2-yl)carbamate

DBU (14 mg, 88.8 umol, 13.4 uL) and BOP (39 mg, 88.8 umol) followed bymethylamine (2 M in THF, 22 mL) were added to a solution of tert-butyl(2-(6-chloro-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)propan-2-yl)carbamate(20.0 mg, 59.2 umol) in DMF (1 mL) and the mixture was stirred at 25° C.for 1 hour. The reaction mixture was diluted with water (15 mL) andextracted with EA (15 mL×3). The combined organic layers were washedwith brine (15 mL×3), dried over anhydrous sodium sulfate, filtered andconcentrated to give the title compound (20.0 mg, 96% yield) as a whitesolid which was used for the next step without further purification. MS(ES+) C₁₇H₂₃ClN₄O₂ requires 350, found 351 [M+H]⁺.

Step 5: Tert-butyl(2-(6-((5-cyano-6-isopropylpyrazine-2-yl)amino)-1-(methylamino)-2,7-naphthyridin-4-yl)propan-2-yl)carbamate

2-(Dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl(BrettPhos) (6 mg, 11.4 umol) and BrettPhos Pd G4 (10 mg, 11.4 umol)were added to a mixture of tert-butyl(2-(6-chloro-1-(methylamino)-2,7-naphthyridin-4-yl)propan-2-yl)carbamate(40 mg, 114 umol), 5-amino-3-isopropylpyrazine-2-carbonitrile (20 mg,123 umol) and potassium acetate (34 mg, 342 umol) in dioxane (2 mL). Thesolution was degassed and purged with N₂ for 3 times, and then themixture was stirred at 100° C. for 1 hour under an atmosphere of N₂. Thereaction mixture was diluted with water (15 mL) and extracted with EA(15 mL×3). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified by prep-TLC(silica, petroleum ether:EA=1:1) to give the title compound (30 mg, 55%yield) as a yellow solid. MS (ES+) C₂₅H₃₂N₈O₂ requires 476, found 477[M+H]⁺

Step 6:5-((5-(2-Aminopropan-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)amino)-3-isopropylpyrazine-2-carbonitrile

Hydrochloric acid in dioxane (4M, 1 mL) was added to a solution oftert-butyl(2-(6-((5-cyano-6-isopropylpyrazine-2-yl)amino)-1-(methylamino)-2,7-naphthyridin-4-yl)propan-2-yl)carbamate(25 mg, 52.5 umol) in dioxane (1 mL) and the solution was stirred at 25°C. for 10 minutes. The reaction mixture was concentrated and the residuewas purified by reverse phase prep-HPLC (column: Luna C18 150*25 5 u;mobile phase: [water(0.075% TFA)-MeCN]; B %: 5%-35%, 9 min) to give thetitle compound (14.9 mg, 74% yield) as a yellow solid. MS (ES+) C₂₀H₂₄N₈requires 376, found 377 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ ppm 9.49 (s,1H), 9.08 (s, 1H), 8.28 (s, 1H), 7.56 (s, 1H), 3.55-3.46 (m, 1H), 3.24(s, 3H), 2.00 (s, 6H), 1.42 (d, J=7.2 Hz, 6H).

Example 7:2-((5-(2-Aminopropan-2-yl)-8-methoxy-2,6-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(46)

Step 1: 4-bromo-7-chloro-1-(1-ethoxyvinyl)-2,6-naphthyridine

Pd(PPh₃)₄ (313 mg, 271 umol) was added to a mixture of4-bromo-7-chloro-1-iodo-2,6-naphthyridine (Intermediate 32, 1.0 g, 2.71mmol) and tributyl(1-ethoxyvinyl)stannane (1.0 g, 2.77 mmol, 935 uL) intoluene (20 mL). The solution was degassed and purged with nitrogen for3 times, and then the mixture was stirred at 100° C. for 16 h under anatmosphere of nitrogen. The reaction mixture was quenched by addition ofsaturated potassium fluoride solution (50 mL), and then diluted withwater (20 mL) and extracted with EA (50 mL×3). The combined organiclayers were dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by flash-column chromatography (petroleum ether:EA=1:0 to 10:1)to give the title compound (640 mg, 75% yield) as a yellow solid. ¹H NMR(400 MHz, CDCl₃): δ ppm 9.43 (s, 1H), 8.79 (s, 1H), 8.30 (d, J=0.8 Hz,1H), 4.88-4.85 (m, 1H), 4.72-4.69 (m, 1H), 4.15-4.08 (m, 2H), 1.49 (t,J=6.8 Hz, 3H).

Step 2: 1-(4-Bromo-7-chloro-2,6-naphthyridin-1-yl)ethan-1-one

HCl in dioxane (4 M, 6 mL) and water (1 mL) were added to4-bromo-7-chloro-1-(1-ethoxyvinyl)-2,6-naphthyridine (640 mg, 2.04 mmol)and the solution was stirred at 60° C. for 2 h. The reaction mixture wasbasified by the addition of saturated aqueous sodium bicarbonatesolution (10 mL) followed by addition of water (20 mL). The aqueouslayer was extracted with EA (20 mL×3). The combined organic layers weredried over anhydrous sodium sulfate, filtered and concentrated. Theresidue was purified by flash-column chromatography (petroleumether:EA=1:0 to 10:1) to give the title compound (550 mg, 94% yield) asa yellow solid.

Step 3: 1-(7-Chloro-4-methoxy-2,6-naphthyridin-1-yl)ethan-1-one

Potassium carbonate (799 mg, 5.78 mmol) was added to a solution of1-(4-bromo-7-chloro-2,6-naphthyridin-1-yl)ethan-1-one (550 mg, 1.93mmol) in methanol (15 mL) and the solution was stirred at 25° C. for 16h. The reaction mixture was concentrated, diluted with water (30 mL) andextracted with EA (30 mL×3). The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to give the title compound (410 mg, 90% yield) as a yellowsolid which was used for next step without further purification. ¹H NMR(400 MHz, CDCl₃): δ ppm 9.51 (s, 1H), 9.10 (d, J=1.2 Hz, 1H), 8.28 (s,1H), 4.23 (s, 3H), 2.80 (s, 3H).

Step 4: 2-(7-Chloro-4-methoxy-2,6-naphthyridin-1-yl)propan-2-ol

Methylmagnesium bromide (3 M in THF, 2 mL) was added to a solution of1-(7-chloro-4-methoxy-2,6-naphthyridin-1-yl)ethan-1-one (410 mg, 1.73mmol) in tetrohydrofuran (15 mL) at 0° C. under an atmosphere ofnitrogen. The solution was stirred at 0° C. for 10 minutes. The reactionmixture was quenched by addition of water (25 mL) and extracted with EA(25 mL×3). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by flash-column chromatography(petroleum ether:EA=1:0 to 3:1) to give the title compound (110 mg, 22%yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ ppm 9.53 (d, J=0.8Hz, 1H), 8.21 (s, 1H), 8.09 (s, 1H), 5.38 (s, 1H), 4.13 (s, 3H), 1.78(s, 6H).

Step 5: 1-(2-Azidopropan-2-yl)-7-chloro-4-methoxy-2,6-naphthyridine

Indium bromide (224 mg, 633 umol) and trimethylsilyl azide (91.0 mg, 791umol) were added to a solution of2-(7-chloro-4-methoxy-2,6-naphthyridin-1-yl)propan-2-ol (80.0 mg, 317umol) in 1, 2-dichloroethane (3 mL) under an atmosphere of nitrogen. Themixture was stirred at 60° C. for 16 h. The reaction mixture was dilutedwith water (15 mL) and extracted with dichloromethane (15 mL×3). Thecombined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by prep-TLC (petroleum ether:EA=3:1) to give thetitle compound (30.0 mg, 32% yield) as a yellow solid. MS (ES+)C₁₂H₁₂ClN₅O requires 277, found 278 [M+H]⁺

Step 6:2-((5-(2-Azidopropan-2-yl)-8-methoxy-2,6-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

2-(Dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl(BrettPhos) (12 mg, 21.6 umol) and BrettPhos Pd G4 (10 mg, 10.8 umol)were added to a mixture of1-(2-azidopropan-2-yl)-7-chloro-4-methoxy-2,6-naphthyridine (30 mg, 108umol), 2-amino-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(Intermediate 2, 22.0 mg, 113 umol) and potassium acetate (32.0 mg, 324umol) in dioxane (2 mL). The solution was degassed and purged withnitrogen 3 times, and then the mixture was stirred at 100° C. for 1 hourunder an atmosphere of nitrogen. The reaction mixture was concentratedand the residue was purified by prep-TLC (petroleum ether:EA=1:1) togive the title compound (20.0 mg, 43% yield) as a yellow solid. MS (ES+)C₂₂H₂₃N₇O₃ requires 433, found 434 [M+H]⁺.

Step 7:2-((5-(2-Aminopropan-2-yl)-8-methoxy-2,6-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

Pd/C (20 mg, 10% purity) was added to a solution of2-((5-(2-azidopropan-2-yl)-8-methoxy-2,6-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(20 mg, 46.1 umol) in EA (6 mL) under an atmosphere of nitrogen. Thesuspension was degassed under vacuum and purged with hydrogen severaltimes. The mixture was stirred under hydrogen (15 psi) at 50° C. for 3h. The reaction mixture was filtered and concentrated. The residue waspurified by prep-TLC (methanol:EA=1:10) to give the title compound (5.8mg, 28% yield) as a yellow solid. MS (ES+) C₂₂H₂₅N₅O₃ requires 407,found 408 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ ppm 9.43 (s, 1H), 8.14 (d,J=8.8 Hz, 1H), 8.06 (s, 1H), 7.17 (d, J=8.4 Hz, 1H), 4.13 (s, 3H), 3.22(s, 2H), 1.92 (s, 6H), 1.54 (s, 6H).

Example 8: (7S,8R)-2-((5-(2-aminopropan-2-yl)-8-cyclopropoxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(66)

Step 1: Methyl 6-chloro-1-cyclopropoxy-2,7-naphthyridine-4-carboxylate

[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane complex (1.09 g, 1.335 mmol) was added to a mixture of4-bromo-6-chloro-1-cyclopropoxy-2,7-naphthyridine (4 g, 13.35 mmol) andtriethylamine (2.233 ml, 16.02 mmol) in MeOH (30 ml) and DMF (15 ml).The reaction vessel was capped under CO (50 psi) and allowed to stir at50° C. After 2 h, the reaction mixture was evaporated to dryness and theresidue was purified using flash-column chromatography (0-15%EA/hexanes) to give the title compound (2.31 g, 62% yield) as a whitesolid. MS (ES+) C₁₃H₁₁ClN₂O₃ requires 278, found 279 [M+H]⁺

Step 2: 2-(6-Chloro-1-cyclopropoxy-2,7-naphthyridin-4-yl)propan-2-ol

Methylmagnesium bromide (3.47 ml, 10.41 mmol) was added to a solution ofmethyl 6-chloro-1-cyclopropoxy-2,7-naphthyridine-4-carboxylate (580 mg,2.08 mmol) in THE (20 ml). After 1 h, the reaction mixture was dilutedwith saturated aqueous NH₄Cl solution and extracted with EA. The organiclayers were dried, filtered, and evaporated. The residue was purifiedusing flash-column chromatography (0-40% EA/hexanes) to give the titlecompound (393 mg, 67.7% yield). MS (ES+) C₁₄H₁₅ClN₂O₂ requires 278,found 279 [M+H]⁺

Step 3: 4-(2-Azidopropan-2-yl)-6-chloro-1-cyclopropoxy-2,7-naphthyridine

Indium(III) bromide (6.36 g, 17.94 mmol) and azidotrimethylsilane (4.72ml, 35.9 mmol) were added to a solution of2-(6-chloro-1-cyclopropoxy-2,7-naphthyridin-4-yl)propan-2-ol (2.5 g,8.97 mmol) in CH₂Cl₂ (80 ml) at 0° C. and the reaction mixture wasallowed to stir overnight. An additional 1 equivalent each ofIndium(III) bromide and azidotrimethylsilane were added and the reactionmixture was heated to 40° C. for 48 h. The reaction was filtered throughcelite and evaporated. The residue was purified using flash-columnchromatography (0-20% EA/hexanes) to give the title compound (1.9 g,69.7% yield). MS (ES+) C₁₄H₁₄ClN₅O requires 303, found 304 [M+H]⁺

Step 4: (7S,8R)-2-((5-(2-azidopropan-2-yl)-8-cyclopropoxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

Chloro{[brettphos][2-(2-aminoethylphenyl)palladium(II)]}/[brettphos](0.57 g, 0.63 mmol) was added to a mixture of (7S,8R)-2-amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(Intermediate 17, 1.323 g, 6.88 mmol),4-(2-azidopropan-2-yl)-6-chloro-1-cyclopropoxy-2,7-naphthyridine (1.9 g,6.26 mmol) and potassium acetate (3.07 g, 31.3 mmol) in dioxane (60 ml).The reaction vessel was capped under N₂ and heated at 100° C. After 30min the reaction was filtered and evaporated. The residue was thenpurified using flash-column chromatography (0-80% EA/hexanes) to givethe title compound (1.74 g, 60% yield). ¹H NMR (400 MHz, DMSO-d₆) δ10.76 (s, 1H), 9.25 (s, 1H), 9.18 (s, 1H), 8.21 (s, 1H), 8.09 (d, J=8.7Hz, 1H), 7.37 (d, J=8.7 Hz, 1H), 4.59 (p, J=6.3 Hz, 1H), 4.51 (dq,J=6.3, 4.1, 3.3 Hz, 1H), 3.05-2.93 (m, 1H), 1.82 (d, J=2.0 Hz, 5H), 1.44(d, J=7.1 Hz, 3H), 1.37 (d, J=6.5 Hz, 3H), 0.89-0.78 (m, 4H). MS (ES+)C₂₄H₂₅N₇O₃ requires 459, found 460 [M+H]⁺.

Step 5: (7S,8R)-2-((5-(2-aminopropan-2-yl)-8-cyclopropoxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

Pd/C (3 g, 10%) was added to a solution of (7S,8R)-2-((5-(2-azidopropan-2-yl)-8-cyclopropoxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(10.76 g, 23.42 mmol) in 100 ml of EA under an atmosphere of nitrogen.The suspension was degassed under vacuum and purged with hydrogenseveral times. The reaction mixture was stirred under hydrogen at roomtemperature overnight. The reaction mixture was then transferred to apressure flask and heated at 50 psi and 50° C. with an additional 1.8 gof Pd/C until starting material was consumed. The reaction mixture wascooled to room temperature, filtered, and evaporated. The residue waspurified via flash-column chromatography (0-10% MeOH/DCM) to give thetitle compound (3.7 g, 36.4% yield). MS (ES+) C₂₄H₂₇N₅O₃ requires 433,found 434 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.61 (s, 1H), 9.38 (s,1H), 9.19 (d, J=0.7 Hz, 1H), 8.20 (s, 1H), 8.06 (d, J=8.7 Hz, 1H), 7.36(d, J=8.7 Hz, 1H), 5.73 (s, 1H), 4.63-4.52 (m, 1H), 4.52-4.43 (m, 1H),3.03-2.92 (m, 1H), 1.64 (d, J=2.0 Hz, 6H), 1.39 (dd, J=24.8, 6.8 Hz,6H), 0.85-0.78 (m, 4H).

Example 9:2-((5-(2-Aminopropan-2-yl)-8-cyclobutoxy-2,7-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(72)

Step 1: 4-(2-Azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-ol

Hydrochloric (6 M, 240 uL) was added to a solution of4-(2-azidopropan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine(Intermediate 31a, 200 mg, 720 umol) in tetrahydrofuran (1 mL) and thesolution was stirred at 25° C. for 16 h. The reaction mixture wasdiluted with water (20 mL) and extracted with EA (20 mL×3). The combinedorganic layers were dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by flash-column chromatography to give the title compound (130mg, 68% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 11.90(s, 1H), 9.20 (s, 1H), 8.02 (s, 1H), 7.43 (d, J=3.2 Hz, 1H), 1.67 (s,6H).

Step 2: 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine

Phosphorus oxychloride (2.86 g, 18.7 mmol, 1.7 mL) was added to4-(2-azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-ol (130 mg, 493 umol)and the solution was stirred at 110° C. for 1 hour. The reaction mixturewas concentrated and the residue was dissolved in EA (10 mL). Themixture was diluted with saturated aqueous sodium bicarbonate solution(20 mL) and extracted with EA (10 mL×3). The combined organic layerswere dried over anhydrous sodium sulfate, filtered and concentrated togive the title compound (110 mg, 79% yield) as a yellow solid which wasused for next step without further purification. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 9.61 (d, J=0.8 Hz, 1H), 8.63 (s, 1H), 8.47 (s, 1H), 1.84(s, 6H).

Step 3: 4-(2-Azidopropan-2-yl)-6-chloro-1-cyclobutoxy-2,7-naphthyridine

Potassium carbonate (132 mg, 957 umol) was added to a solution of4-(2-azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine (90.0 mg, 319umol) and cyclobutanol (69.0 mg, 957 umol) in MCCN (5 mL) and stirred at60° C. for 4 h. The reaction mixture was concentrated; diluted withwater (20 mL) and extracted with EA (20 mL×3). The combined organiclayers were dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by prep-TLC to give the title compound (50.0 mg, 49% yield) asyellow oil. ¹H NMR (400 MHz, CDCl₃): δ ppm 9.45 (s, 1H), 8.32 (s, 1H),8.17 (s, 1H), 5.48-5.37 (m, 1H), 2.62-2.52 (m, 2H), 2.36-2.23 (m, 2H),1.98-1.87 (m, 1H), 1.79 (s, 6H), 1.77-1.71 (m, 1H).

Step 4: 4-(2-Azidopropan-2-yl)-6-chloro-1-cyclobutoxy-2,7-naphthyridine

2-(Dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl(BrettPhos) (10 mg, 18.9 umol) and BrettPhos Pd G4 (9 mg, 9.44 umol)were added to a mixture of2-amino-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(Intermediate 2, 20 mg, 104 umol),4-(2-azidopropan-2-yl)-6-chloro-1-cyclobutoxy-2,7-naphthyridine (30 mg,94.4 umol) and potassium acetate (28 mg, 283 umol) in dioxane (2 mL).The solution was degassed and purged with nitrogen for 3 times, and thenthe mixture was stirred at 100° C. for 1 hour under nitrogen atmosphere.The reaction mixture was concentrated and the residue was purified byprep-TLC to give the title compound (26.3 mg, 60% yield) as a yellowsolid. MS (ES+) C₂₅H₂₉N₅O₃ requires 447, found 448 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): δ ppm 9.37 (s, 1H), 9.32 (s, 1H), 8.15 (d, J=8.8 Hz, 1H),8.10 (s, 1H), 7.21 (d, J=8.8 Hz, 1H), 5.48-5.35 (m, 1H), 3.22 (s, 2H),2.62-2.51 (m, 2H), 2.34-2.22 (m, 2H), 1.96-1.91 (m, 1H), 1.85 (s, 6H),1.82-1.74 (m, 1H), 1.53 (s, 6H).

Example 10:N-(2-(2-Fluoropropan-2-yl)pyrimidin-4-yl)-8-methoxy-5-(2-(methylamino)propan-2-yl)-2,7-naphthyridin-3-amine(17)

Step 1:N-(2-(2-Fluoropropan-2-yl)pyrimidin-4-yl)-8-methoxy-5-(2-(methylamino)propan-2-yl)-2,7-naphthyridin-3-amine

Pd/C (10 mg, 10% purity) and formaldehyde (16.4 mg, 202 umol) were addedunder nitrogen to a solution of5-(2-azidopropan-2-yl)-N-(2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-8-methoxy-2,7-naphthyridin-3-amine(100 mg, 252 umol) in methanol (20 mL). The suspension was degassedunder vacuum and purged with hydrogen several times. The mixture wasstirred under hydrogen (15 psi) at 25° C. for 16 h. The reaction mixturewas filtered and concentrated under reduce pressure to give a residue.The residue was purified by reverse phase prep-HPLC to give the titlecompound (16.0 mg, 16% yield) as a white solid. MS (ES+) C₂₀H₂₅FN₆Orequires 384, found 385 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ ppm 9.37 (s,1H), 9.31 (s, 1H), 8.39 (d, J=6.0 Hz, 1H), 8.03 (s, 1H), 7.29 (d, J=56.0Hz, 1H), 4.13 (s, 3H), 2.07 (s, 3H), 1.83 (s, 3H) 1.78 (s, 3H), 1.69 (s,6H)

Example 11:2-((8-Methoxy-5-(pyrrolidin-2-yl)-2,7-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(50)

Step 1: Tert-butyl2-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)pyrrolidine-1-carboxylate

6-Chloro-4-iodo-1-methoxy-2,7-naphthyridine (0.4 g, 1.248 mmol),Nickel(II) chloride dimethoxyethane adduct (0.016 g, 0.075 mmol),1-[(tert-Butoxy)carbonyl]pyrrolidine-2-carboxylic acid (0.537 g, 2.496mmol), (4,4′-Di-t-butyl-2,2′bipyridine)bis[3,5-difluoro-2-(5-trifluoromethyl-2-pyridinyl-kN)phenyl-kC]iridium(III)hexafluorophosphate (0.014 g, 0.012 mmol), and cesium carbonate (1.220g, 3.74 mmol) were combined in a 40 mL vial. DMF (24.96 ml) was addedand the reaction mixture was surrounded by Blue LED light and stirred atambient temperature for 16 h. The reaction mixture was diluted with EAand washed with water, saturated brine solution, dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The residue waspurified by flash-column chromatography (20-100% EA:Hexanes). Desiredfractions were identified, combined, and concentrated in vacuo to affordthe title compound. MS (ES+) C₁₈H₂₂ClN₃O₃ requires 363, found 364[M+H]⁺.

Step 2: Tert-butyl2-(6-((7,7-dimethyl-5-oxo-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)amino)-1-methoxy-2,7-naphthyridin-4-yl)pyrrolidine-1-carboxylate

Tert-butyl2-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)pyrrolidine-1-carboxylate(104 mg, 0.286 mmol),2-amino-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(Intermediate 2, 50 mg, 0.26 mmol), potassium acetate (77 mg, 0.780mmol), and 1:1 mix of BrettPhos Pd G4 admixture and2-(Dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl(38 mg, 0.026 mmol) were combined in a vial and capped under N₂. Dioxane(1.3 ml) as added and the mixture was heated to 100° C. After 4 h,another 38 mg of 1:1 catalyst mix was added and heating continued foranother 12 h. The mixture was then cooled to ambient temperature andconcentrated in vacuo. The residue was purified by flash-columnchromatography (20-100% EA:Hexanes). Desired fractions were identified,combined, and concentrated in vacuo to afford the title compound. MS(ES+) C₂₈H₃₃N₅O₅ requires 519, found 520 [M+H]⁺.

Step 3:2-((8-Methoxy-5-(pyrrolidin-2-yl)-2,7-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

Tert-butyl2-(6-((7,7-dimethyl-5-oxo-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)amino)-1-methoxy-2,7-naphthyridin-4-yl)pyrrolidine-1-carboxylate(20 mg, 0.038 mmol) was stirred in 5:1 DCM:TFA for 2 h. The reactionmixture was diluted with EA and carefully washed with saturated aqueoussodium bicarbonate, saturated aqueous brine solution, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by flash-column chromatography. Desired fractionswere identified, combined, and concentrated in vacuo to afford the titlecompound. MS (ES+) C₂₃H₂₅N₅O₃ requires 419, found 420 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 10.64 (s, 1H), 9.18 (d, J=0.8 Hz, 1H), 8.49 (s,1H), 8.05 (d, J=8.7 Hz, 1H), 7.38-7.31 (m, 2H), 4.22 (t, J=6.7 Hz, 1H),4.06 (s, 3H), 3.21 (s, 2H), 3.15 (s, 1H), 3.09 (dt, J=10.4, 6.4 Hz, 1H),2.98 (dt, J=10.1, 6.7 Hz, 1H), 2.24-2.09 (m, 1H), 1.84-1.70 (m, 3H),1.43 (s, 6H).

Example 12:2-((5-(2-Aminopropan-2-yl)-8-chloroisoquinolin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(104)

Step 1: 2-(3-Amino-8-chloroisoquinolin-5-yl)propan-2-ol

n-Butyllithium (2.5 mol/L in n-hexane, 6.21 mL) was added to a solutionof 5-bromo-8-chloroisoquinolin-3-amine (Journal of Medicinal Chemistry,60(9), 3755-3775; 2017) (800 mg, 3.11 mmol) and TMEDA (1.81 g, 15.5mmol) in toluene (10 mL) at −70° C. The reaction mixture was stirred for0.5 h at −70° C., then acetone (1.80 g, 31.1 mmol) was added to thereaction mixture. The reaction mixture was stirred for 0.5 h at −70° C.,then was quenched by addition of aqueous saturated NH₄Cl solution (30mL) at −70° C. After warming to ambient temperature, the reactionmixture was extracted with EA 80 mL (40 mL×2), washed with brine 40 mL(20 mL×2), dried over sodium sulfate, filtered and concentrated to givea residue. The residue was purified by flash-column chromatography onsilica gel (gradient elution, 10% to 50% ethyl acetate-petroleum ether)to give the title compound (200 mg, 25% yield) as a yellow solid. MS(ES+) C₁₂H₁₃ClN₂O requires 236, found 237 [M+H]⁺.

Step 2: 5-(2-Azidopropan-2-yl)-8-chloroisoquinolin-3-amine

TMSN₃ (107 mg, 929 umol) was added to a solution of2-(3-Amino-8-chloroisoquinolin-5-yl)propan-2-ol (200 mg, 845 umol) andindium bromide (599 mg, 1.69 mmol) in DCM (8 mL). The reaction mixturewas stirred at 25° C. for 16 h, then was diluted with water (20 mL) andextracted with DCM (20 mL×3). The combined organic layers were driedover anhydrous sodium sulfate, filtered and concentrated to give thetitle compound (210 mg, crude) as a yellow solid. MS (ES+) C₁₂H₁₂ClN₅requires 261, found 262 [M+H]⁺.

Step 3:2-((5-(2-Azidopropan-2-yl)-8-chloroisoquinolin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

Pd₂(dba)₃ (70.0 mg, 76.4 umol), XantPhos (88.4 mg, 153 umol) and cesiumcarbonate (747 mg, 2.29 mmol) were added to a solution of5-(2-azidopropan-2-yl)-8-chloroisoquinolin-3-amine (200 mg, 764 umol)and 2-chloro-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(Steps 1-3, Intermediate 2) (162 mg, 764 umol) in dioxane (5 mL). Thereaction mixture was stirred at 80° C. for 1 h, then was cooled toambient temperature, filtered, and concentrated to give a residue. Theresidue was purified by column chromatography (SiO2, PE/EA=10/1 to 1/1)to give the title compound (210 mg, 60% yield) as a yellow solid. MS(ES+) C₂₂H₂₁ClN₆O₂ requires 436, found 437 [M+H]⁺.

Step 4:2-((5-(2-Aminopropan-2-yl)-8-chloroisoquinolin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

Zinc (67.4 mg, 1.03 mmol) and acetic acid (124 mg, 2.06 mmol) were addedto a solution of2-((5-(2-azidopropan-2-yl)-8-chloroisoquinolin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(90 mg, 206 umol) in THE (5 mL). The reaction mixture was stirred at 15°C. for 0.5 h, then was filtered and concentrated to give a residue. Theresidue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm*5um; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B %: 38%-68%, 10 min) togive the title compound (25 mg, 30% yield) as a yellow solid. MS (ES+)C₂₂H₂₃ClN₄O₂ requires 410, found 411 [M+H]⁺. ¹H-NMR (400 MHz, CD₃OD): δppm 9.61 (s, 1H), 9.42 (s, 1H), 8.12 (d, J=8.8 Hz, 1H), 7.79 (d, J=8.0Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 3.24 (s, 2H),1.87 (s, 6H), 1.55 (s, 6H).

Example 13:(7S,8R)-2-((5-((R)-2-Amino-1-hydroxypropan-2-yl)-8-cyclopropoxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-oneand(7S,8R)-2-((5-((S)-2-amino-1-hydroxypropan-2-yl)-8-cyclopropoxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(139 and 140)

Step 1: 6-Chloro-1-cyclopropoxy-4-(prop-1-en-2-yl)-2,7-naphthyridine

A mixture of 4-bromo-6-chloro-1-cyclopropoxy-2,7-naphthyridine(Intermediate 33 and 34, step 1)(5.00 g, 16.7 mmol),2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.09 g, 18.4mmol), Pd(dppf)Cl₂ (1.22 g, 1.67 mmol), and potassium carbonate (4.61 g,33.4 mmol) in dioxane (30 mL) and water (6 mL) was degassed and purgedwith nitrogen 3 times. The reaction mixture was stirred at 60° C. for 2h, then was concentrated to give a residue. The residue was purified bycolumn chromatography (SiO₂, PE/EA=10/1) to give the title compound(2.50 g, 9.59 mmol, 57% yield) as a white solid.

Step 2:6-Chloro-1-cyclopropoxy-4-(2-methyloxiran-2-yl)-2,7-naphthyridine

m-CPBA (4.48 g, 22.1 mmol, 85% purity) was added to a solution of6-chloro-1-cyclopropoxy-4-(prop-1-en-2-yl)-2,7-naphthyridine (2.30 g,8.82 mmol) in DCM (100 mL). The reaction mixture was stirred at 25° C.for 12 h, then was quenched by addition of aqueous saturated sodiumsulfite solution (50 mL) and extracted with DCM (50 mL). The organiclayer was dried over sodium sulfate, filtered and concentrated to give aresidue. The residue was purified by column chromatography (SiO₂,PE/EA=5/1) to give the title compound (750 mg, 2.71 mmol, 31% yield) asa white solid.

Step 3:2-Azido-2-(6-chloro-1-cyclopropoxy-2,7-naphthyridin-4-yl)propan-1-ol

TMSN₃ (625 mg, 5.42 mmol, 713 uL) and InBr₃ (1.92 g, 5.42 mmol) wereadded to a solution of6-chloro-1-cyclopropoxy-4-(2-methyloxiran-2-yl)-2,7-naphthyridine (300mg, 1.08 mmol) in 1,2-dichloroethane (10 mL). The reaction mixture wasstirred at 50° C. for 0.5 h, then was poured into water (100 mL) andextracted with EA (30 mL×3). The organic layers were dried over sodiumsulfate, filtered and concentrated to give a residue. The residue waspurified by column chromatography (SiO2, PE:EA=5:1 to 1:1) to give thetitle compound (60.0 mg) as a yellow solid.

Step 4:(7S,8R)-2-((5-(2-Azido-1-hydroxypropan-2-yl)-8-cyclopropoxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

BrettPhos (Pd, G4) (10 mg, 10.9 μmol), BrettPhos (8.39 mg, 15.6 μmol)and potassium acetate (46.0 mg, 469 μmol) were added to a solution of2-azido-2-(6-chloro-1-cyclopropoxy-2,7-naphthyridin-4-yl)propan-1-ol(50.0 mg) and(7S,8R)-2-amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(Intermediate 17×36.1 mg, 188 μmol) in dioxane (2 mL). The reactionmixture was stirred at 60° C. for 1 h, then was concentrated to give aresidue. The residue purified by prep-TLC (ethyl acetate) to give thetitle compound (40.0 mg, crude) as a yellow solid.

Step 5:(7S,8R)-2-((5-(2-Amino-1-hydroxypropan-2-yl)-8-cyclopropoxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

Pd(OH)₂/C (10.0 mg, 20% purity) was added to a solution of(7S,8R)-2-((5-(2-azido-1-hydroxypropan-2-yl)-8-cyclopropoxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(40.0 mg, crude) in EA (2 mL). The reaction mixture was stirred at 40°C. under hydrogen (15 psi) for 12 h, then was filtered and concentratedto give a residue. The residue purified by prep-TLC (EA:MeOH=10:1) togive the title compound (25.0 mg, 50.7 μmol, 60% yield) as a yellowsolid.

Step 6:(7S,8R)-2-((5-((R)-2-Amino-1-hydroxypropan-2-yl)-8-cyclopropoxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-oneand(7S,8R)-2-((5-((S)-2-amino-1-hydroxypropan-2-yl)-8-cyclopropoxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

(7S,8R)-2-((5-(2-Amino-1-hydroxypropan-2-yl)-8-cyclopropoxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(20.0 mg, 44.5 μmol) was separated by SFC (column: Daicel Chiralpak IC(250 mm*30 mm, 10 um); mobile phase: [0.1% NH₄OH in EtOH]) to give(7S,8R)-2-((5-((R)-2-Amino-1-hydroxypropan-2-yl)-8-cyclopropoxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-oneor(7S,8R)-2-((5-((S)-2-amino-1-hydroxypropan-2-yl)-8-cyclopropoxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(first eluting isomer, 3.00 mg, 11% yield) as a yellow solid and(7S,8R)-2-((5-((R)-2-Amino-1-hydroxypropan-2-yl)-8-cyclopropoxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-oneor(7S,8R)-2-((5-((S)-2-amino-1-hydroxypropan-2-yl)-8-cyclopropoxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(second eluting isomer 3.00 mg, 10% yield) as a yellow solid. Firsteluting isomer: MS (ES+) C₂₄H₂₇N₅O₄ requires 449, found 450 [M+H]⁺.¹H-NMR (400 MHz, CD₃OD): δ ppm 9.33 (s, 1H), 8.92 (s, 1H), 8.18 (d,J=8.8 Hz, 1H), 8.01 (s, 1H), 7.35 (d, J=8.4 Hz, 1H), 4.68-4.65 (m, 1H),4.54 (m, 1H), 4.42-4.38 (m, 1H), 4.11-4.08 (m, 1H), 3.03-3.01 (m, 1H),1.99 (s, 3H), 1.53-1.45 (m, 6H), 0.91 (m, 4H). Second eluting isomer: MS(ES+) C₂₄H₂₇N₅O₄ requires 449, found 450 [M+H]⁺. ¹H-NMR (400 MHz,CD₃OD): δ ppm 9.33 (s, 1H), 8.94 (s, 1H), 8.18 (d, J=8.8 Hz, 1H), 8.01(s, 1H), 7.34 (d, J=8.4 Hz, 1H), 4.69-4.67 (m, 1H), 4.55-4.50 (m, 1H),4.39-4.36 (m, 1H), 4.16-4.13 (m, 1H), 3.06-3.03 (m, 1H), 1.99 (s, 3H),1.51-1.46 (m, 6H), 0.91 (m, 4H).

Example 14:2-((5-(2-(Cyclobutylamino)propan-2-yl)-8-methoxy-2,7-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(158)

Step 1: 2-(6-Chloro-1-methoxy-2,7-naphthyridin-4-yl)propan-2-amine

Zinc (589 mg, 9.00 mmol) and acetic acid (1.08 g, 18.0 mmol, 1.03 mL)were added to a solution of4-(2-azidopropan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine(Intermediate 31a) (500 mg, 1.80 mmol) in THE (5.00 mL). The reactionmixture was stirred at 60° C. for 1 h, then was cooled to ambienttemperature and treated with saturated aqueous ammonium hydroxidesolution to adjust to pH-7. The reaction mixture was filtered andconcentrated to give a residue. The residue was purified by columnchromatography (SiO₂, PE/EA=1:0 to 3:2) to give the title compound (272mg, 1.08 mmol, 60% yield) was obtained as a white solid.

Step 2:N-(2-(6-Chloro-1-methoxy-2,7-naphthyridin-4-yl)propan-2-yl)cyclobutanamine

A solution of 2-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)propan-2-amine(50.0 mg, 199 μmol), cyclobutanone (55.7 mg, 795 μmol, 59.4 μL) andacetic acid (11.9 mg, 199 μmol, 11.4 μL) in MeOH (2.00 mL) was stirredat 15° C. for 0.5 h, then sodium cyanoborohydride (37.5 mg, 596 μmol)was added. The reaction mixture was stirred at 15° C. for 0.5 h., thenwas concentrated to give a residue. The residue was purified by prep-TLC(PE:EA=5:1) to give the title compound (60.0 mg, 196 μmol, 99% yield) aswhite oil. MS (ES+) C₁₆H₂₀ClN₃O requires 305, found 306 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): δ ppm 9.38 (s, 1H), 9.16 (d, J 3.8 Hz, 1H), 8.08 (s,1H), 4.13 (s, 3H), 2.87-2.79 (m, 1H), 2.03-1.96 (m, 2H), 1.68-1.59 (m,2H), 1.55 (s, 6H), 1.52-1.45 (m, 2H), 0.08-0.06 (m, 1H).

Step 3:2-((5-(2-(Cyclobutylamino)propan-2-yl)-8-methoxy-2,7-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

A mixture ofN-(2-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)propan-2-yl)cyclobutanamine(40.0 mg, 131 μmol), Intermediate 2 (25.1 mg, 131 μmol), BrettPhos (Pd,G4) (12.0 mg, 13.1 μmol), BrettPhos (7.02 mg, 13.1 μmol) and potassiumacetate (64.2 mg, 654 μmol) in dioxane (1.00 mL) was stirred at 100° C.for 1 h. The reaction mixture was then concentrated to give a residue.The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875*30 mm*3 um; mobile phase: [water(0.1% TFA)-ACN]; B %: 25%-35%, 7 min)to give the title compound (27.9 mg, 45% yield) as a yellow solid. MS(ES+) C₂₆H₃₁N₅O₃ requires 461, found 462 [M+H]⁺. ¹H NMR (400 MHz,6d-DMSO): δ ppm 10.80 (s, 1H), 9.38 (s, 1H), 9.14 (s, 2H), 8.83 (s, 1H),8.17-8.13 (m, 2H), 7.41-7.39 (m, 1H), 4.11 (s, 3H), 3.09 (s, 2H), 2.52(s, 1H), 2.12-2.05 (m, 2H), 1.99 (s, 5H), 1.92-1.87 (m, 2H), 1.69-1.58(m, 2H), 1.45 (s, 6H)

Example 15:2-((8-Cyclopropoxy-5-(2-((2-hydroxyethyl)amino)propan-2-yl)-2,7-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(177)

Step 1: 2-(6-Chloro-1-cyclopropoxy-2,7-naphthyridin-4-yl)propan-2-amine

Zinc (323 mg, 4.94 mmol) was added to a solution of4-(2-azidopropan-2-yl)-6-chloro-1-cyclopropoxy-2,7-naphthyridine(Example 8, Steps 1-3)(300 mg, 988 μmol) and acetic acid (5297 mg, 4.94mmol) in THF (8 mL). The reaction mixture was stirred at 25° C. for 10min, then was filtered and concentrated. The residue was purifiedflash-column MeOH=3:1) to give the title compound (200 mg, 73% yield) asa yellow solid. MS (ES+) C₁₄H₁₆ClN₃O requires 277, found 278 [M+H]⁺.

Step 2: Methyl(2-(6-chloro-1-cyclopropoxy-2,7-naphthyridin-4-yl)propan-2-yl)glycinate

Potassium carbonate (179 mg, 1.30 mmol) was added to a mixture of2-(6-Chloro-1-cyclopropoxy-2,7-naphthyridin-4-yl)propan-2-amine (180 mg,648 μmol) and methyl 2-bromoacetate (297 mg, 1.94 mmol) inN,N-dimethylformamide (4 mL). The reaction mixture was stirred at 60° C.for 2 h. then was diluted with water (20 mL) and extracted with EA (20mL×3). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated to give a residue. The residue waspurified by flash-column chromatography on silica gel (PE:EA=1:0 to 3:1)to give the title compound (170 mg, 75% yield) as a white solid.

Step 3:2-((2-(6-Chloro-1-cyclopropoxy-2,7-naphthyridin-4-yl)propan-2-yl)amino)ethan-1-ol

Lithium borohydride (24.9 mg, 1.14 mmol) was added to a solution ofmethyl(2-(6-chloro-1-cyclopropoxy-2,7-naphthyridin-4-yl)propan-2-yl)glycinate(80.0 mg, 229 μmol) in THF (4 mL). The reaction mixture was stirred at25° C. for 0.5 h, then was was quenched by addition of water (10 mL) andextracted with EA (10 mL×3). The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated to give a residue. The residue was purified by prep-TLC(PE:EA=1:2) to give the title compound (30.0 mg, 41% yield) as a whitesolid. MS (ES+) C₁₆H₂₀ClN₃O₂ requires 321, found 322 [M+H]⁺.

Step 4:2-((8-Cyclopropoxy-5-(2-((2-hydroxyethyl)amino)propan-2-yl)-2,7-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

BrettPhos (5.00 mg, 9.32 μmol), BrettPhos (Pd, G4) (8.58 mg, 9.32 μmol)and potassium acetate (22.9 mg, 233 μmol) were added to a mixture of2-((2-(6-chloro-1-cyclopropoxy-2,7-naphthyridin-4-yl)propan-2-yl)amino)ethan-1-ol(30.0 mg, 93.2 μmol) and2-amino-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(Intermediate 2)(26.9 mg, 140 μmol) in dioxane (3 mL). The reactionmixture was stirred at 80° C. for 2 h, then was concentrated to give aresidue. The residue was purified by prep-TLC (EA:MeOH=10:1), then wasfurther purified by prep-HPLC (column: Phenomenex Gemini NX-C18 (75*30mm*3 um); mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %:33% 63%, 10 min) to give the title compound (6.70 mg, 15% yield) as ayellow solid. MS (ES+) C₂₆H₃₁N₅O₄ requires 477, found 478 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD): δ ppm 9.91 (s, 1H), 9.23 (s, 1H), 8.18-8.07 (m, 1H),8.02 (s, 1H), 7.27-7.14 (m, 1H), 4.51-4.36 (m, 1H), 3.55-3.41 (m, 2H),3.26 (s, 2H), 2.47-2.37 (m, 2H), 1.82-1.66 (m, 6H), 1.54 (s, 6H), 0.89(s, 4H).

Example 16:(7S,8R)-2-((5-((R)-2-Amino-1-methoxypropan-2-yl)-8-cyclopropoxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-oneand(7S,8R)-2-((5-((S)-2-amino-1-methoxypropan-2-yl)-8-cyclopropoxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(184)

Steps 1-2:(7S,8R)-2-((5-(2-Amino-1-methoxypropan-2-yl)-8-cyclopropoxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

The title compound was prepared from4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-cyclopropoxy-2,7-naphthyridine(mixture of Intermediates 68 and 69 prior to separation (after Step 3)and(7S,8R)-2-amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(Intermediate 17) using a similar procedure as described in Steps 4 and5 of Example 13.

Step 3:(7S,8R)-2-((5-((R)-2-Amino-1-methoxypropan-2-yl)-8-cyclopropoxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-oneand(7S,8R)-2-((5-((S)-2-amino-1-methoxypropan-2-yl)-8-cyclopropoxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

(7S,8R)-2-((5-(2-Amino-1-methoxypropan-2-yl)-8-cyclopropoxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(25.0 mg) was separated by SFC (column: Daicel Chiralpak AS (250 mm*30mm, 10 um); mobile phase: [0.1% NH₃H₂O MeOH]) to give(7S,8R)-2-((5-((R)-2-Amino-1-methoxypropan-2-yl)-8-cyclopropoxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-oneor(7S,8R)-2-((5-((S)-2-amino-1-methoxypropan-2-yl)-8-cyclopropoxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(first eluting isomer, 8.00 mg, 32% yield) as a yellow solid and(7S,8R)-2-((5-((R)-2-Amino-1-methoxypropan-2-yl)-8-cyclopropoxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-oneor(7S,8R)-2-((5-((S)-2-amino-1-methoxypropan-2-yl)-8-cyclopropoxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(second eluting isomer, 9.00 mg, 37% yield) as a yellow solid. MS (ES+)C₂₅H₂₉N₅O₄ requires 463, found 464 [M+H]⁺. ¹H-NMR (400 MHz, CD₃OD): δppm 9.24 (s, 1H), 9.20 (s, 1H), 8.19 (s, 1H), 8.13 (d, J=8.8 Hz, 1H),7.29 (d, J=8.8 Hz, 1H), 4.69-4.63 (m, 1H), 4.45-4.43 (m, 1H), 3.97-3.95(m, 1H), 3.83-3.81 (m, 1H), 3.35 (s, 3H), 3.06-2.99 (m, 1H), 1.74 (s,3H), 1.52-1.46 (m, 6H), 0.93-0.87 (m, 4H).

Example 17:(S)-2′-((5-(1-Aminopropyl)-8-methoxyisoquinolin-3-yl)amino)-7′,7′-dimethyl-5′H,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridin]-5′-oneor(R)-2′-((5-(1-aminopropyl)-8-methoxyisoquinolin-3-yl)amino)-7′,7′-dimethyl-5′H,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridin]-5′-one(207)

Step 1:(S)—N—((R)-1-(3-((7′,7′-Dimethyl-5′-oxo-5′H,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridin]-2′-yl)amino)-8-methoxyisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamideor(S)—N—((S)-1-(3-((7′,7-dimethyl-5′-oxo-5′H,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridin]-2′-yl)amino)-8-methoxyisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamide

A mixture of(S)—N—((S)-1-(3-chloro-8-methoxyisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamideor(S)—N—((R)-1-(3-chloro-8-methoxyisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamide(Intermediate 73, 20 mg, 56.4 umol),2′-amino-7′,7′-dimethyl-5′H,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridin]-5′-one(Intermediate 85)(14.8 mg, 67.6 umol), BrettPhos (6.05 mg, 11.3 umol),BrettPhos (Pd, G4) (5.19 mg, 5.64 umol) and potassium acetate (16.6 mg,169 umol) in dioxane (2.5 mL) was degassed and purged with nitrogen 3times. The reaction was stirred at 100° C. for 1 h, then was filteredand concentrated to give a residue. The residue was purified by prep-TLC(PE:EA=0:1) to give the title compound (20 mg, 65% yield) as a yellowsolid. MS (ES+) C₂₉H₃₆N₄O₄S requires 536, found 537 [M+H]⁺.

Step 2:(S)-2′-((5-(1-Aminopropyl)-8-methoxyisoquinolin-3-yl)amino)-7′,7′-dimethyl-5′H,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridin]-5′-oneor(R)-2′-((5-(1-aminopropyl)-8-methoxyisoquinolin-3-yl)amino)-7′,7′-dimethyl-5′H,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridin]-5′-one

HCl (4 M in dioxane, 9.32 uL) was added to a solution of(S)—N—((R)-1-(3-((7′,7′-dimethyl-5′-oxo-5′H,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridin]-2′-yl)amino)-8-methoxyisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamideor(S)—N—((S)-1-(3-((7′,7′-dimethyl-5′-oxo-5′H,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridin]-2′-yl)amino)-8-methoxyisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamide(product from previous step, 20 mg, 37.3 umol) in dioxane (1 mL). Thereaction mixture was stirred at 25° C. for 0.5 h, then was concentratedto give a residue. The residue was purified by prep-HPLC (column:3_Phenomenex Luna C18 75×30 mm×3 μm; mobile phase: [water (0.05%HCl)-ACN]; B %: 21%-41%, 6.5 min) to give the title compound (6.3 mg,39% yield) as a white solid. MS (ES+) C₂₉H₃₆N₄O₄S requires 432, found433 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ ppm 9.75-9.52 (m, 1H), 8.34 (d,J=8.8 Hz, 1H), 8.25 (s, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.22 (d, J=2.0 Hz,1H), 7.19 (d, J=0.8 Hz, 1H), 5.03-4.94 (m, 1H), 4.17 (s, 3H), 2.30-2.09(m, 2H), 1.65-1.56 (m, 2H), 1.55-1.48 (m, 2H), 1.46 (s, 6H), 1.04-0.97(m, 3H).

Example 18:(7S,8R)-2-((5-((R)-1-Amino-1-cyclopropylethyl)-8-((trans)-3-hydroxycyclobutoxy)-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-oneand(7S,8R)-2-((5-((S)-1-amino-1-cyclopropylethyl)-8-((trans)-3-hydroxycyclobutoxy)-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(193)

Steps 1-6:(7S,8R)-2-((5-(1-Azido-1-cyclopropylethyl)-8-((trans)-3-(benzyloxy)cyclobutoxy)-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

The title compound was prepared from4-bromo-1,6-dichloro-2,7-naphthyridine andtrans-3-(benzyloxy)cyclobutan-1-ol using a similar procedure asdescribed in Steps 1-3 of Intermediate 33 and Steps 1,2, and 4 (exceptusing Intermediate 17) of Example 3B. ¹H NMR (400 MHz, CD₃OD): δ ppm9.40 (s, 1H), 9.07 (d, J=14.4 Hz, 1H), 8.38 (d, J=10.0 Hz, 1H), 8.25 (d,J=8.8 Hz, 1H), 8.07-8.01 (m, 1H), 7.40-7.29 (m, 5H), 5.67-5.56 (m, 1H),4.64-4.52 (m, 1H), 4.50 (s, 2H), 4.48-4.40 (m, 1H), 3.11-2.95 (m, 1H),2.75-2.64 (m, 2H), 2.63-2.52 (m, 2H), 1.62-1.52 (m, 10H), 0.81-0.40 (m,4H).

Step 7:(7S,8R)-2-((5-(1-Amino-1-cyclopropylethyl)-8-((trans)-3-(benzyloxy)cyclobutoxy)-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

To a solution of(7S,8R)-2-((5-(1-azido-1-cyclopropylethyl)-8-((trans)-3-(benzyloxy)cyclobutoxy)-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(180 mg, 297 μmol) in EA (5 mL) was added platinum dioxide (54.0 mg, 238μmol). The suspension was degassed under vacuum and purged with hydrogenseveral times. The mixture was stirred under hydrogen (15 psi) at 25° C.for 16 h, then was filtered and concentrated to give a residue. Theresidue was purified by flash silica gel chromatography (gradientelution, 0100% EA/PE) to give the title compound (75.0 mg, 44% yield) asa yellow solid.

Step 8:(7S,8R)-2-((5-(1-Amino-1-cyclopropylethyl)-8-((trans)-3-hydroxycyclobutoxy)-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

To a solution of(7S,8R)-2-((5-(1-amino-1-cyclopropylethyl)-8-((trans)-3-(benzyloxy)cyclobutoxy)-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(60.0 mg, 104 μmol, 1 eq) in DCM (2 mL) was added boron trichloride (901mg, 7.69 mmol) at 0° C. The mixture was stirred at 25° C. for 18 h, thenwas quenched with saturated aqueous sodium bicarbonate solution (10 mL)and extracted with DCM (10 mL×3). The combined organic layers were driedover anhydrous sodium sulfate, filtered and concentrated to give aresidue. The residue was purified by prep-TLC (EA:MeOH=10:1) to give thetitle compound as a mixture of diastereomers. (20.0 mg, 40% yield). Themixture was separated by SFC (column: Daicel Chiralpak OD (250 mm*30 mm,10 um); mobile phase: [0.1% NH₃H₂O MeOH]) to give(7S,8R)-2-((5-((R)-1-Amino-1-cyclopropylethyl)-8-((trans)-3-hydroxycyclobutoxy)-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-oneor(7S,8R)-2-((5-((S)-1-amino-1-cyclopropylethyl)-8-((trans)-3-hydroxycyclobutoxy)-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(first eluting isomer, 10.0 mg, 50% yield) as a yellow solid and(7S,8R)-2-((5-((R)-1-Amino-1-cyclopropylethyl)-8-((trans)-3-hydroxycyclobutoxy)-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-oneor(7S,8R)-2-((5-((S)-1-amino-1-cyclopropylethyl)-8-((trans)-3-hydroxycyclobutoxy)-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one(second eluting isomer, 10.0 mg, 50%) as a yellow solid. MS (ES+)C₂₇H₃₁N₅O₄ requires 489, found 490 [M+H]⁺.

¹H NMR (400 MHz, CD₃OD): δ ppm 9.40 (s, 1H), 9.01 (s, 1H), 8.16 (d,J=8.8 Hz, 1H), 8.09 (s, 1H), 7.41 (d, J=8.8 Hz, 1H), 5.64-5.53 (m, 1H),4.70-4.55 (m, 2H), 3.06-2.94 (m, 1H), 2.65-2.45 (m, 4H), 1.80 (s, 3H),1.65-1.56 (m, 1H), 1.51-1.44 (m, 6H), 0.79-0.48 (m, 4H).

Example 19: Inhibition of MAP4K₁ Biochemical Enzymatic Activity

MAP4K₁ (HPK1) and relevant off-target enzymatic activity was monitoredusing the Perkin Elmer electrophoretic mobility shift technologyplatform—the EZReader 2. Fluorescent labeled substrate peptide wasincubated in the presence of kinase and ATP, and in the presence ofdosed compound, such that each dose of compound resulted in a reflectiveproportion of the peptide to be phosphorylated. Within the linear,steady-state phase of the kinase enzymatic reaction, the mixed pool ofphosphorylated (product) and non-phosphorylated (substrate) peptides waspassed through the microfluidic system of the PerkinElmer EZ Reader 2,under an applied electric potential difference. The presence of thephosphate group on the product peptide provided a difference in mass andcharge between that of the substrate peptide, resulting in a separationof the substrate and product pools in the sample (Perrin et al. 2010).As the product and substrate peptide mixture passes the lasers withinthe instrument, these pools are detected (λ_(ex)=488 nm, λ_(ent)=568 nm)and resolved as separate peaks. The ratio between these peaks reflectsthe activity of the compound at that concentration, in that well, underthose conditions.

Enzyme Activity Inhibition Assay Protocol:

Inhibitors were dissolved in 100% DMSO at a stock concentration of 10mM. A 100×, 10-point, 4-fold serial dilution of each inhibitor wascreated in 100% DMSO either manually or on a Hamilton STAR liquidhandler, starting at a relevant concentration, usually 1 mM. A volume of0.130 μL of each concentration was transferred to the relevant wells ofa 384-well plate (Greiner 781 201) in duplicate using a TTPLabtechMosquito nano-litre dispenser. Using a Multidrop Combi, the remainingconstituents of the kinase reaction were added to the 130 nL of dosedcompound as follows (see table below for final reaction details):

Enzyme activity assays at the ^(APP)K_(M) for ATP or 1 mM ATP: In eachwell of a 384-well plate, 0.1-15 nM of untreated enzyme was incubated ina total of 13 μL of buffer (100 mM HEPES pH 7.5, 0.015% Brij 35, 10 mMMgCl₂, 1 mM DTT) with 1.5 μM fluorescent peptid and 20-1000 μM ATP, at25° C., for 60-180 minutes in the presence or absence of a dosedconcentration series of compound (1% DMSO final concentration). Thekinase reactions were stopped by the addition of 70 μl of Stop buffer(100 mM HEPES pH 7.5, 0.015% Brij 35, 35 mM EDTA and 0.2% of CoatingReagent 3 (Caliper Lifesciences)). The plates were read on a CaliperEZReader 2 as described above.

TABLE 2 Kinase Reaction Conditions Substrate Enzyme ATP Peptide & KinaseEnzyme Concen- Concen- Concen- Reaction (Source) tration tration trationTime HPK 1 0.5 nM   26 μM S6K2tide, 120 min. (Invitrogen) 1.5 μM HPK 10.25 nM 1000 μM S6K2tide, 120 min. (Invitrogen) 1.5 μM LCK 12 nM   26 μMFL4tide,  60 min. (Invitrogen) 1.5 μM HGK 0.1 nM   50 μM FL25tide,  60min. (Invitrogen) 1.5 μM GLK 15 nM   20 μM PKAtide, 180 min. (Signal- 2μM Chem)

S6K₂tide; Carna Biosciences (5-FAM-Proprietary Sequence-CONH2)

FL4tide; Perkin Elmer (5-FAM-EGIYGVLFKKK (SEQ ID NO: 1)-CONH₂)

FL25tide; Perkin Elmer (5-FAM-VDGKEIYNTIRRK (SEQ ID NO: 2)-CONH₂)

PKAtide; Anaspec Peptide Co. (5-FAM-GRTGRRNSI (SEQ ID NO: 3)-CONH₂)

Perrin D, Frémaux C, Shutes A. Capillary microfluidic electrophoreticmobility shift assays: application to enzymatic assays in drugdiscovery. Expert Opin Drug Discov. 2010, 5(1):51-63.

The results obtained ins these experiments for compounds preparedaccording to the examples are summarized in Table 3 below. Forbiochemical MAP4K₁ activity, the following designations are used: <0.30nM=A; 0.31-1.0 nM=B; 1.1-10.0 nM=C; and >10.0 nM=D. For IL-2measurement: <35.0 nM=A; 35.1-45.0 nM=B; 45.1-55.0=C nM; and >55.0 nM=D.

TABLE 3 Com- MAP4K1 MAP4K1 IL-2 IL-2 pound IC₅₀ IC₅₀ EC₅₀ EC₅₀ No. (nM)(nM) (nM) (nM)   1 21.35 D ND ND   2 1.60 C 18.9 A   3 0.36 B 108.3 D  4 0.42 B ND ND   5 0.37 B 37.1 B   6 3.31 C ND ND   7 0.91 B 21.7 A  8 11.14 D ND ND   9 0.55 B 21.1 A  10 2.73 C ND ND  11 0.33 B 10.9 A 12 0.31 B 11.0 A  13 0.29 A ND ND  14 0.64 B 51.0 C  15 0.68 B 30.9 A 16 2.50 C ND ND  17 4.02 C ND ND  18 0.40 B ND ND  19 0.30 A 27.3 A  200.73 B 51.1 C  21 0.85 B 48.7 C  22 0.50 B 36.6 B  23 0.11 A 4.9 A  240.47 B 11.3 A  25 0.29 A 3.3 A  26 0.55 B 14.0 A  27 0.30 A ND ND  280.67 B 31.4 A  29 3.98 C ND ND  30 3.57 C ND ND  31 5.88 C ND ND  3211.46 D ND ND  33 0.13 A 9.3 A  34 0.24 A 45.6 B  35 0.41 B 23.5 A  360.17 A 15.3 A  37 0.14 A 1.9 A  38 0.20 A 5.8 A  39 0.85 B 16.2 A  400.15 A 4.0 A  41 0.57 B 22.7 A  42 0.86 B 13.6 A  43 0.23 A 8.3 A  441.20 C 22.0 A  45 1.03 B 70.3 D  46 0.94 B 34.3 A  47 13.58 D ND ND  481.72 C 135.5 D  49 1.01 B ND ND  50 52.56 D ND ND  51 0.26 A ND ND  520.33 B ND ND  53 0.36 B 17.2 A  54 0.25 A 9.3 A  55 0.18 A 11.6 A  560.10 A 6.6 A  57 0.16 A 5.1 A  58 0.39 B 20.4 A  59 3.35 C 56.7 D  600.18 A 10.3 A  61 0.15 A 3.5 A  62 0.55 B ND ND  63 6.46 C ND ND  640.44 B 42.9 B  65 0.56 B ND ND  66 0.18 A 8.1 A  67 0.12 A 6.2 A  680.27 A 29.5 A  69 0.88 B 52.8 C  70 0.35 B 20.6 A  71 0.11 A 7.9 A  720.41 B 35.5 B  73 0.22 A 23.7 A  74 0.12 A 22.2 A  75 0.09 A 7.3 A  760.12 A 6.5 A  77 0.65 B 32.5 A  78 0.19 A 11.6 A  79 0.26 A 9.3 A  800.08 A 4.1 A  81 ND ND ND ND  82 0.16 A 20.8 A  83 0.19 A 28.7 A  841.32 C ND ND  85 0.22 A 36.1 B  86 2.03 C ND ND  87 0.44 B 31.6 A  880.16 A 11.5 A  89 5.12 C ND ND  90 3.42 C ND ND  91 0.10 A 15.1 A  920.25 A 15.4 A  93 3.65 C ND ND  94 0.14 A 23.5 A  95 4.54 C ND ND  960.14 A 9.4 A  97 0.36 B ND ND  98 19.1 D ND ND  99 0.13 A ND ND 100 2.60C ND ND 101 0.11 A 20.8 A 102 1.87 C 28.7 A 103 0.11 A 3.1 A 104 0.13 AND ND 105 2.09 C 50.6 C 106 0.61 B 41.3 B 107 0.62 B ND ND 108 0.98 B NDND 109 0.21 A 9.8 A 110 0.55 B 33.9 A 111 16.77 D 2657 D 112 0.23 A 19.6A 113 0.58 B 32.7 A 114 0.88 B 25.6 A 115 7.39 D 231.5 D 116 2.14 C 64.9D 117 0.24 A 16.0 A 118 1.28 C 81.7 D 119 0.12 A ND ND 120 0.50 B ND ND121 0.90 B ND ND 122 0.16 A ND ND 123 0.20 A 7.6 A 124 0.24 A 7.4 A 1251.84 C ND ND 126 ND ND ND ND 127 0.17 A 21.0 A 128 1.09 C ND ND 129 0.11A ND ND 130 0.46 B ND ND 131 0.46 B 35.2 B 132 0.18 A 12.9 A 133 5.86 C53.8 C 134 1.33 C ND ND 135 0.54 B 31.6 A 136 0.39 B 40.5 B 137 0.46 BND ND 138 0.27 A 13.8 A 139 2.25 C ND ND 140 13.94 D ND ND 141 0.42 B21.6 A 142 0.20 A ND ND 143 0.31 B ND ND 144 3.89 C ND ND 145 1.77 C NDND 146 0.25 A 60.4 D 147 0.27 A 45.2 B 148 0.11 A ND ND 149 0.20 A ND ND150 5.24 C ND ND 151 0.22 A 27.3 A 152 0.42 B 54.4 D 153 2.61 C ND ND154 0.08 A 11.0 A 155 0.97 B 88.4 D 156 0.10 A 13.6 A 157 0.14 A 21.3 A158 6.46 C ND ND 159 0.39 B 27.4 A 160 1.25 C ND ND 161 1.37 C ND ND 1620.24 A ND ND 163 0.25 A ND ND 164 7.35 C ND ND 165 1.26 C ND ND 166 0.25A 40.0 B 167 0.05 A 9.4 A 168 0.15 A 41.3 B 169 2.94 C ND ND 170 0.07 A6.8 A 171 0.07 A 27.6 A 172 4.47 C 74.8 D 173 1.72 C ND ND 174 2.90 C28.2 A 175 35.12 D ND ND 176 0.80 B 20.9 A 177 6.52 C ND ND 178 0.29 A58.7 D 179 2.12 C ND ND 180 15.44 D ND ND 181 0.18 A 15.1 A 182 2.92 C38.8 B 183 26.35 D 3.1 A 184 0.27 A 33.4 A 185 0.35 B ND ND 186 0.40 BND ND 187 0.06 A ND ND 188 0.09 A 6.8 A 189 0.16 A 45.8 C 190 0.19 A NDND 191 0.53 B ND ND 192 0.19 A 6.6 A 193 0.10 A ND ND 194 0.33 B ND ND195 0.27 A ND ND 196 0.10 A 19.0 A 197 0.34 B ND ND 198 0.27 A ND ND 1990.36 B ND ND 200 0.48 B ND ND 201 0.14 A ND ND 202 0.62 B ND ND 203 0.50B ND ND 204 0.22 A 29.8 A 205 0.35 B 112.9 D 206 0.19 A ND ND 207 0.22 AND ND 208 0.70 B 96.0 D 209 0.39 B ND ND 210 0.23 A 176.8 D

Example 20: T Cell Enhancement of Cytokines

Isolation and Expansion of T Cells from Whole Blood

T cells are isolated from whole blood of healthy donors byimmunomagnetic negative selection following manufacture's protocol(StemCell Technologies, human T cell isolation kit). Purity of isolatedcells is assessed by flow cytometry and yields 95-98% CD3⁺ T cells. Forexpansion of T cells, 1×10⁶ cells/well are plated in serum free cellexpansion media (ThermoFisher) containing 30 U of recombinant human IL2(R&D) and stimulated with 25 ul of CD3/CD28 beads (Invitrogen) in 24well plates for 3-4 days. T cells are then expanded in 175 cm flasks andmaintained at a cell density of 1 to 2.5×10⁶ cells/ml days by additionof ⅔ of fresh media every 2-3 days. After 10-14 days, cells are frozenin BamBanker freezing media (Thermo) and stored in liquid nitrogen.Phenotypic analysis of expanded T cells by flow cytometry, routinelyshows 60% cells are CD8⁺ T cells upon freezing.

Cytokine Measurement

For IL2 measurement, expanded CD3⁺ T cells are dispensed at 100Kcells/well (cultured in X-VIVO 10 Serum-free media) and are stimulatedwith plate-bound anti-CD3 and soluble anti-CD28 in the presence ofvehicle or compound of the disclosure at various concentrations for 24h. As outlined in the manufacturer's protocol (Cisbio), 16 μL ofconditioned media is transferred to a white 384-well low volume plate.Following a 24 h incubation with the anti-IL2 antibodies, the homogenoustime resolved fluorescence (HTRF) is measured.

Example 21: Inhibition of Anti-Tumor Activity in a Syngeneic Mouse Model

Generation of the MCA205 Syngeneic Xenograft Anti-Tumor Efficacy Study

Six to eight-week-old female, C₅₇BL/6 mice (Jackson Labs, Bar Harbor,Me.) are implanted subcutaneously on the left flank with 1×10⁶ MCA205cells/mouse. After tumors reach an average volume of 50 mm³, mice arerandomized into treatment groups, 10 mice per group, with tumors in thesize range of 30-70 mm³. Compounds of the disclosure 10-30 mg/kg,anti-mouse PD-L1 mAb (B7H₁, clone #10F.9G2 Bio-X-cell, Lebanon, N.H.)and vehicle either alone or in different combinations are administeredto tumor bearing mice. Reduction in tumor volume is measured [mm³] overtime.

EQUIVALENTS

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The disclosure includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Thedisclosure includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the disclosure encompasses all variations, combinations,and permutations in which one or more limitations, elements, clauses,and descriptive terms from one or more of the listed claims areintroduced into another claim. For example, any claim that is dependenton another claim can be modified to include one or more limitationsfound in any other claim that is dependent on the same base claim. Whereelements are presented as lists, e.g., in Markush group format, eachsubgroup of the elements is also disclosed, and any element(s) can beremoved from the group. It should it be understood that, in general,where the disclosure, or aspects of the disclosure, is/are referred toas comprising particular elements and/or features, certain embodimentsof the disclosure or aspects of the disclosure consist, or consistessentially of, such elements and/or features. For purposes ofsimplicity, those embodiments have not been specifically set forth inhaec verba herein. Where ranges are given, endpoints are included.Furthermore, unless otherwise indicated or otherwise evident from thecontext and understanding of one of ordinary skill in the art, valuesthat are expressed as ranges can assume any specific value or sub-rangewithin the stated ranges in different embodiments of the disclosure, tothe tenth of the unit of the lower limit of the range, unless thecontext clearly dictates otherwise.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation, many equivalents to the specificembodiments of the disclosure described and claimed herein. Suchequivalents are intended to be encompassed by the following claims.

What is claimed is:
 1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: A¹ and A² are selected from N and CH; A³ is selected from CH and N; X is selected from C₁₋₃ alkyl, OR⁶, NHR⁷ and halogen; B is selected from CR¹¹ and N, Y is selected from N and CR¹², and the bond between Y and B is a double bond; or B is C(O), Y is NR¹⁴, and the bond between Y and B is a single bond; or Y and B taken together form a 5 to 7-membered heterocycle or C₅₋₆ cycloalkyl, and the bond between Y and B is a double bond, wherein said heterocycle or cycloalkyl is optionally substituted with 1-6 R⁸; each R⁸ is independently selected from C₁₋₃ alkyl and OH, or two R⁸ attached to the same carbon form an oxo, or two R⁸ attached to the same carbon atom taken together with the carbon atom to which they are attached form a C₃₋₅ cycloalkyl, or two R⁸ attached to two adjacent carbon atoms taken together with the two adjacent carbon atoms to which they are attached form a C₃₋₆ cycloalkyl, wherein said alkyl and cycloalkyl are optionally substituted with 1-6 halogen; R¹ and R² are each independently selected from hydrogen, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, and 3 to 5-membered heterocycle, wherein said alkyl and cycloalkyl are optionally substituted with OH, C₁₋₆alkoxy or 1-6 halogen; or R¹ and R², taken together with the atoms to which they are attached, form a 4 to 6-membered heterocycle or C₃₋₆ cycloalkyl; R³ and R⁴ are each independently selected from hydrogen, C₁₋₆ alkyl substituted with OR¹⁶, C₁₋₆ alkyl, C₃₋₆ cycloalkyl and 4 to 6-membered heterocycle; or R³ and R⁴, taken together with the atoms to which they are attached, form a C₃₋₆ cycloalkyl or 4 to 6-membered heterocycle; or R¹ and R³, taken together with the atoms to which they are attached, form a 3 to 6-membered heterocycle; R⁶ is selected from C₁₋₃ alkyl, C₃₋₆ cycloalkyl and 4 to 6-membered heterocycle, wherein said alkyl, cycloalkyl, and heterocycle are optionally substituted with 1-3 R⁹; R⁷ is selected from hydrogen, C₁₋₃ alkyl, C₃₋₅ cycloalkyl and 4 to 6-membered heterocycle, wherein said alkyl, cycloalkyl, and heterocycle are optionally substituted with 1-3 R⁹; R⁹ is selected from C₁₋₃ alkyl, C₃₋₆ cycloalkyl substituted with halogen, halogen, C₁₋₃ alkoxy, and OH; R¹¹ is selected from hydrogen, COON, CN, halogen, and C₁₋₃ alkoxy; R¹² is selected from C₁₋₅ alkyl, C₄₋₆ cycloalkyl, 3 to 6-membered heterocycle, NHR¹³, NR¹³R¹³ and OR¹³, wherein said alkyl, cycloalkyl or heterocycle is optionally substituted with OH, NH₂, 1-4 halogen or R¹⁵; each R¹³ is independently selected from C₁₋₆ alkyl and C₃₋₆ cycloalkyl, wherein said alkyl or cycloalkyl is optionally substituted with halogen; R¹⁴ is selected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl and 4 to 6-membered heterocycle, wherein said alkyl, cycloalkyl or heterocycle is optionally substituted with 1-6 halogen; R¹⁵ is OH, C₁₋₃ alkyl or C₃₋₅ cycloalkyl; and R¹⁶ is H or C₁₋₃ alkyl.
 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: X is selected from OR⁶, NHR⁷ and halogen; and R³ and R⁴ are each independently selected from hydrogen, C₁₋₆ alkyl substituted with OH, C₁₋₆ alkyl, C₃₋₆ cycloalkyl and 4 to 6-membered heterocycle; or R³ and R⁴, taken together with the atoms to which they are attached, form a C₃₋₆ cycloalkyl or 4 to 6-membered heterocycle; or R¹ and R³, taken together with the atoms to which they are attached, form a 3 to 6-membered heterocycle.
 3. The compound of claim 2, wherein the compound is represented by Formula II, Formula III or Formula IV:

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim 3, wherein the compound is represented by Formula V or VI:

or a pharmaceutically acceptable salt thereof, wherein E is CH₂, NH, or O; R⁸ is C₁₋₃ alkyl, and n is 0 to 4; two R⁸ groups attached to the same carbon atom taken together with the carbon atom to which they attach form a C₃₋₅ cycloalkyl; or two R⁸ groups attached to two adjacent carbon atoms taken together with the two adjacent carbon atoms to which they attached form a C₄₋₆ cycloalkyl.
 5. The compound of claim 4, wherein the compound is represented by Formula V(B) or VI(B):

or a pharmaceutically acceptable salt thereof.
 6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R⁸ is methyl and n is 0, 1, 2, 3, or
 4. 7. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein two R⁸ attached to the same carbon atom taken together with the carbon atom to which they are attached form a cyclopropyl; or two R⁸ attached to two adjacent carbon atoms taken together with the two adjacent carbon atoms to which they are attached form a cyclopentyl.
 8. The compound of claim 3, wherein the compound is represented by Formula VII, VIII or IX:

or a pharmaceutically acceptable salt thereof.
 9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein: R¹¹ is CN; and R¹² is selected from isopropyl, fluoropropyl, trifluoroisopropyl, isobutyl, tert-butyl, isopropyloxy, methylpyrrolidine, methylazetidine, and hydroxycyclohexyl.
 10. The compound of claim 3, wherein the compound is represented by Formula X:

or a pharmaceutically acceptable salt thereof.
 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R¹⁴ is isobutyl.
 12. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein X is OR⁶, and R⁶ is selected from methyl, ethyl, propyl, isopropyl, trifluoroethyl, trifluoroisopropyl, difluoroethyl, difluoropropyl, difluoroisopropyl, oxetanyl, tetrahydrofuranyl, cyclobutyl, and cyclopropyl, wherein cyclopropyl is optionally substituted with methyl or one or two fluoro, wherein cyclobutyl is optionally substituted with OH, and wherein oxetanyl is optionally substituted with methyl.
 13. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein X is NHR⁷, and R⁷ is selected from methyl, ethyl, cyclopropyl and cyclobutyl.
 14. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein X is methyl.
 15. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R³ and R⁴ are each independently selected from hydrogen, methyl, methyl substituted with OCH₃, ethyl, hydroxymethyl, cyclopropyl and cyclobutyl.
 16. The compound of claim 1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 17. The compound of claim 1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 18. The compound of claim 1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 19. The compound of claim 1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 20. The compound of claim 1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 21. The compound of claim 1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 22. The compound of claim 1, wherein the compound is:

a pharmaceutically acceptable salt thereof.
 23. The compound of claim 1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 24. The compound of claim 1, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 25. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 